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Li Q, Chen Y, Zhu Y, Cui X, Pan J, Li X, Liu X. Immune cells mediate the effect of plasma lipidomes on IgA nephropathy: a Mendelian randomization study. Ren Fail 2025; 47:2498631. [PMID: 40328660 PMCID: PMC12057791 DOI: 10.1080/0886022x.2025.2498631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 03/31/2025] [Accepted: 04/19/2025] [Indexed: 05/08/2025] Open
Abstract
BACKGROUND IgA nephropathy (IgAN) is a leading cause of chronic kidney disease, often associated with dyslipidemia and immune dysfunction. This study employs Mendelian randomization (MR) to investigate the causal relationship between plasma lipidomes and IgAN, with a focus on the potential mediating role of immune cells. METHODS We analyzed the 179 genetically predicted plasma lipidomes and the IgAN gene using two-sample Mendelian randomization (TSMR) and multivariable MR based on summary-level data from a genome-wide association study, and the results were validated by liquid chromatography-mass spectrometry. Furthermore, we quantified the proportional effect of immune cell-mediated lipidomes on IgAN using TSMR. RESULTS This study identified significant causal relationships of 3 lipidomes on IgAN risk by examining 179 lipidome traits as exposures. To investigate whether the impact of the 3 lipid groups on IgAN is specific, we performed TSMR analyses using 3 lipidomes as exposure factors and 4 nephritides as outcomes. Specifically, only phosphatidylinositol (18:1_20:4) was found to have a significant negative relationship with IgAN incidence (IVW method, p = 0.01, OR = 0.71, 95% CI = 0.55 - 0.92). Our further analysis focused on 8 immune cells associated with IgAN. We identified 2 immune cell phenotypes that may contribute to phosphatidylinositol (18:1_20:4)-mediated IgAN by careful screening. CONCLUSIONS Our findings provide robust genetic evidence supporting a causal link between plasma lipidomes and IgAN, with immune cells acting as potential mediators. Phosphatidylinositol (18:1_20:4) emerges as a promising biomarker for IgAN risk stratification, early detection, and therapeutic intervention. Modulating its plasma levels may offer novel avenues for IgAN management.
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Affiliation(s)
- Quanxin Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Ye Chen
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yahan Zhu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Xiaoyang Cui
- Department of Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jichen Pan
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Xiao Li
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Xiaolin Liu
- National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
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Kula A. Drug Development in Pediatric Chronic Kidney Disease: A Review of Promising Treatments, Old Challenges, and New Strategies. Paediatr Drugs 2025; 27:283-291. [PMID: 39928268 DOI: 10.1007/s40272-025-00684-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/15/2025] [Indexed: 02/11/2025]
Abstract
Youth under the age of 18 years represent a distinct subset of the population living with chronic kidney disease (CKD). The etiology of CKD differs greatly between children and adults, and young people with CKD face an extended lifetime living with their disease. Few rigorous randomized controlled trials in CKD have included people under the age of 18 years. As such, the recent success of CKD trials with sodium glucose co-transporter 2 inhibitors, mineralocorticoid antagonists, dual endothelin agonists, and hypoxia-induced factor prolyl hydroxylase inhibitors have largely not extended to children and adolescents. There are many reasons to believe these medications could prove as transformative in youth as they have in older adults, but trial data are missing. Innovative strategies are required to ensure that trials of recent, and future, agents in youth with CKD are successful.
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Affiliation(s)
- Alexander Kula
- Division of Pediatric Nephrology, Ann and Robert H. Lurie Children's Hospital of Chicago, 225 Chicago Ave, Chicago, IL, 60611, USA.
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Praga M, Caravaca-Fontán F, Da Silva I, Fernández-Juárez G, Gutiérrez E, Sevillano AM, Trimarchi H. Tailored management strategies for IgA nephropathy based on clinical presentations. Nephrol Dial Transplant 2025; 40:874-883. [PMID: 39689916 DOI: 10.1093/ndt/gfae289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Indexed: 12/19/2024] Open
Abstract
The treatment landscape for immunoglobulin A nephropathy is rapidly evolving with the introduction of novel therapies targeting diverse disease pathways. Some have already been approved in different countries, while others are under investigation in randomized controlled trials (RCTs) with encouraging results. However, almost all performed RCTs have included only patients with refractory non-nephrotic proteinuria and preserved renal function. Other clinical presentations (rapidly progressive forms, malignant hypertension, thrombotic microangiopathy, nephrotic syndrome) have received less attention and are systematically excluded from RCTs. In contrast, certain aspects, such as the impact of haematuria or management in special populations (e.g. pregnant patients or transplant recipients), remain underexplored. This review proposes therapeutic algorithms to guide treatment decisions in different clinical scenarios while highlighting gaps in current research.
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Affiliation(s)
- Manuel Praga
- Department of Medicine, Universidad Complutense de Madrid, Madrid, Spain
| | | | - Iara Da Silva
- Department of Nephrology, Hospital Universitario Germans Trias i Pujol, Badalona, Barcelona, Spain
| | | | - Eduardo Gutiérrez
- Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Angel M Sevillano
- Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Hernan Trimarchi
- Department of Nephrology, Hospital Británico de Buenos Aires, Buenos Aires, Argentina
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Vivarelli M, Samuel S, Coppo R, Barratt J, Bonilla-Felix M, Haffner D, Gibson K, Haas M, Abdel-Hafez MA, Adragna M, Brogan P, Kim S, Liu I, Liu ZH, Mantan M, Shima Y, Shimuzu M, Shen Q, Trimarchi H, Hahn D, Hodson E, Pfister K, Alladin A, Boyer O, Nakanishi K. IPNA clinical practice recommendations for the diagnosis and management of children with IgA nephropathy and IgA vasculitis nephritis. Pediatr Nephrol 2025; 40:533-569. [PMID: 39331079 PMCID: PMC11666671 DOI: 10.1007/s00467-024-06502-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 08/08/2024] [Accepted: 08/08/2024] [Indexed: 09/28/2024]
Abstract
IgA nephropathy and IgA vasculitis with nephritis, albeit rare, represent two relatively frequent glomerular conditions in childhood. Compared to adults, pediatric IgA nephropathy has a more acute presentation, most frequently with synpharyngitic macrohematuria and histologically with more intense inflammation and less intense chronic damage. Management of these conditions is controversial and supported by little high-quality evidence. The paucity of evidence is due to the disease heterogeneity, its inter-ethnic variability, and the difficulty of extrapolating data from adult studies due to the peculiarities of the condition in children. IgA vasculitis with nephritis is a kidney manifestation of a systemic disorder, typical of the pediatric age, in which both the diagnosis of kidney involvement and its management are poorly defined, and an interdisciplinary approach is crucial. Both conditions can have a profound and long-lasting impact on kidney function and the global health of affected children. The International Pediatric Nephrology Association has therefore convened a diverse international group of experts from different disciplines to provide guidance on the recommended management of these conditions in children and to establish common definitions and define priorities for future high-quality, evidence-based collaborative studies for the benefit of children.
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Affiliation(s)
- Marina Vivarelli
- Laboratory of Nephrology, Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4 00165, Rome, Italy.
| | - Susan Samuel
- Section of Nephrology, Department of Pediatrics, University of Calgary, Calgary, Canada
| | - Rosanna Coppo
- Fondazione Ricerca Molinette, Regina Margherita Hospital, Turin, Italy
| | | | - Melvin Bonilla-Felix
- Department of Pediatrics, University of Puerto Rico-Medical Sciences Campus, San Juan, , Puerto Rico
| | - Dieter Haffner
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Keisha Gibson
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Mark Haas
- Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | - Marta Adragna
- Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Paul Brogan
- University College London Great Ormond Street Institute of Child Health, London, England, UK
| | - Siah Kim
- Children's Hospital at Westmead, Westmead, Australia
| | - Isaac Liu
- Duke-NUS Medical School and YLLSOM, National University of Singapore, Singapore, Singapore
| | - Zhi-Hong Liu
- Nanjing University School of Medicine, Nanjing, China
| | - Mukta Mantan
- Maulana Azad Medical College, University of Delhi, Delhi, India
| | - Yuko Shima
- Wakayama Medical University, Wakayama, Japan
| | - Masaki Shimuzu
- Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo, Japan
| | - Qian Shen
- Children's Hospital of Fudan University, Shanghai, China
| | | | - Deirdre Hahn
- Children's Hospital at Westmead, Westmead, Australia
| | | | - Ken Pfister
- Department of Pediatrics, University of Calgary, Calgary, Canada
| | - Areefa Alladin
- Department of Pediatrics, University of Calgary, Calgary, Canada
- University of Guyana, Georgetown, Guyana
| | - Olivia Boyer
- Pediatric Nephrology, MARHEA Reference Center, Imagine Institute, Paris Cité University, Necker Children's Hospital, APHP, Paris, France
| | - Koichi Nakanishi
- Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of Ryukyus, Nishihara, Okinawa, Japan
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Guo Y, Shi S, Zhao J, Wang C, Liu Z, Fu S, Chen N, Li G, Wang L, Ni Z, Zhang H, Lai L, Lv J, Zhang H. Prognosis of IgA nephropathy patient with proteinuria remission by supportive therapy: cohort from screening failed Chinese patients in TESTING study. Ren Fail 2024; 46:2398826. [PMID: 39248402 PMCID: PMC11385640 DOI: 10.1080/0886022x.2024.2398826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 08/22/2024] [Accepted: 08/26/2024] [Indexed: 09/10/2024] Open
Abstract
BACKGROUND During the run-in phase of the TESTING study, approximately half of patients with IgA nephropathy (IgAN) were excluded due to proteinuria below 1 g/24 h after intensive supportive therapy. The long-term prognosis of these patients needs further investigation. METHODS 112 screening failed patients in the TESTING study from 10 centers in China were enrolled in this retrospective study. The prognosis of 88 patients, who were excluded because of proteinuria below 1 g/24 h, was analyzed by Landmark Kaplan-Meier analysis. The composite kidney endpoint was defined by a ≥ 50% reduction in eGFR, ESKD (eGFR <15 mL/min per 1.73 m2), chronic dialysis for at least 6 months, or renal transplantation. RESULTS In total, 88 patients were excluded due to proteinuria less than 1 g/24 h. During the follow-up, 73/88 (83.0%) patients received renin-angiotensin system blocker. 72/88 (81.8%) had stable proteinuria remission and did not receive immunosuppressive therapy (IST), and 16/88 (18.2%) received IST because of a relapse of proteinuria. Landmark Kaplan-Meier analysis revealed that, the kidney survival from dialysis or composite kidney outcome of these excluded patients with IST was similar to those without IST during the early stages of follow-up (dialysis, before 60 months, p = 0.778; composite kidney outcome, before 48 months, p = 0.862); whereas the risk for dialysis of patients receiving IST was significantly higher than those without IST after 60 months (OR = 11.3, p = 0.03). Similarly, the risk for the composite kidney outcome of patients receiving IST was also significantly higher than those without IST after 48 months (OR = 5.92, p = 0.029). CONCLUSIONS IgAN patients who maintained a persistent remission of proteinuria after intensive supportive therapy had a much better long-term kidney outcome than those who experienced a relapse of proteinuria and needed IST.
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Affiliation(s)
- Yingman Guo
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Sufang Shi
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Jinghong Zhao
- Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Caili Wang
- The First Affiliated Hospitals of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Zhangsuo Liu
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuxia Fu
- Department of Nephrology, The Second Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Nan Chen
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guisen Li
- Renal Division and Institute of Nephrology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan, China
| | - Lihua Wang
- Division of Nephrology, Shanxi Medical University Second Hospital, Shanxi Kidney Disease Institute, Taiyuan, China
| | - Zhaohui Ni
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Haitao Zhang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Lingyun Lai
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jicheng Lv
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Hong Zhang
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
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Nagasawa H, Suzuki H, Ueda S, Suzuki Y. Dual blockade of endothelin A and angiotensin II type 1 receptors with sparsentan as a novel treatment strategy to alleviate IgA nephropathy. Expert Opin Investig Drugs 2024; 33:1143-1152. [PMID: 39425494 DOI: 10.1080/13543784.2024.2414902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 10/07/2024] [Indexed: 10/21/2024]
Abstract
INTRODUCTION Although immunoglobulin A nephropathy (IgAN) had been discovered more than 50 years ago, 30-40% of IgAN patients still have primary glomerular disease that progresses to end-stage renal disease. However, various treatment strategies for IgAN have rapidly expanded in recent years to include endothelin (ET) receptor antagonists. AREAS COVERED In this review, we discuss the role of the ET-1/ETA receptor axis in the development of IgAN, especially focusing on the potential of sparsentan, a dual ET and angiotensin receptor antagonist as a novel therapy for IgAN. EXPERT OPINION Evaluation of the MEST-C score at the time of renal biopsy in IgAN is important in determining treatment strategies. If lesions are mainly in the acute phase, such as crescents, steroid therapy should be continued. However, if lesions are mainly in the chronic phase, such as glomerulosclerosis, sparsentan rather than steroid or angiotensin II receptor blocker alone may improve renal outcomes. Although further clinical studies are needed to back up these assumptions, appropriate combination of new drugs containing sparsentan and conventional drugs for IgAN treatment at the appropriate disease stage is expected to further inhibit the progression of renal damage.
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Affiliation(s)
- Hajime Nagasawa
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
- Division of Kidney Health and Aging, The Center for Integrated Kidney Research and Advance, Shimane University Faculty of Medicine, Shimane, Japan
| | - Hitoshi Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
- Department of Nephrology, Juntendo University Urayasu Hospital, Chiba, Japan
| | - Seiji Ueda
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
- Division of Kidney Health and Aging, The Center for Integrated Kidney Research and Advance, Shimane University Faculty of Medicine, Shimane, Japan
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
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Filippone EJ, Gulati R, Farber JL. Contemporary review of IgA nephropathy. Front Immunol 2024; 15:1436923. [PMID: 39188719 PMCID: PMC11345586 DOI: 10.3389/fimmu.2024.1436923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/02/2024] [Indexed: 08/28/2024] Open
Abstract
IgA nephropathy (IgAN) is considered the most common primary glomerulonephritis worldwide with a predilection for Asian-Pacific populations and relative rarity in those of African descent. Perhaps 20%-50% of patients progress to kidney failure. The pathogenesis is incompletely understood. Mesangial deposition of immune complexes containing galactose-deficient IgA1 complexed with anti-glycan IgG or IgA antibodies results in mesangial cell activation and proliferation, inflammatory cell recruitment, complement activation, and podocyte damage. Diagnosis requires a biopsy interpreted by the Oxford criteria. Additional pathologic features include podocytopathy, thrombotic microangiopathy, and C4d staining. Biomarkers predicting adverse outcomes include proteinuria, reduced GFR, hypertension, and pathology. Acceptable surrogate endpoints for therapeutic trials include ongoing proteinuria and rate of eGFR decline. The significance of persisting hematuria remains uncertain. The mainstay of therapy is supportive, consisting of lifestyle modifications, renin-angiotensin inhibition (if hypertensive or proteinuric), sodium-glucose-transporter 2 inhibition (if GFR reduced or proteinuric), and endothelin-receptor antagonism (if proteinuric). Immunosuppression should be considered for those at high risk after maximal supportive care. Corticosteroids are controversial with the most positive results observed in Chinese. They carry a high risk of serious side effects. Similarly, mycophenolate may be most effective in Chinese. Other immunosuppressants are of uncertain benefit. Tonsillectomy appears efficacious in Japanese. Active areas of investigation include B-cell inhibition with agents targeting the survival factors BAFF and APRIL and complement inhibition with agents targeting the alternate pathway (Factors B and D), the lectin pathway (MASP-2), and the common pathway (C3 and C5). Hopefully soon, the who and the how of immunosuppression will be clarified, and kidney failure can be forestalled.
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Affiliation(s)
- Edward J. Filippone
- Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - Rakesh Gulati
- Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - John L. Farber
- Department of Pathology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
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Zhao B, Wang M, Cong Y, Song A, Lu J, Xie K, Dai H, Gu L. Urinary exosomal mRNAs as biomarkers for predicting the therapeutic effect of renin-angiotensin system inhibitors in IgA nephropathy patients. Clin Chim Acta 2024; 561:119750. [PMID: 38885756 DOI: 10.1016/j.cca.2024.119750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 02/08/2024] [Accepted: 05/22/2024] [Indexed: 06/20/2024]
Abstract
BACKGROUND Renin-angiotensin system inhibitors (RASi) treatment is the basic therapy for IgA nephropathy (IgAN) patients. However, there is few of biomarker that can predict the efficacy of RASi. This study aimed to find urinary exosomal mRNAs related to the therapeutic effect of RASi in the treatment of proteinuria in IgAN patients. METHODS We divided IgAN patients in screening cohort into A1 (proteinuria increase at 3 months), B1 (proteinuria decrease less than 50 % at 3 months), C1 (proteinuria decrease more than 50 % at 3 months) groups according to changes of proteinuria after treatment. The urinary exosomes were collected before biopsy, RNAs were extracted and analyzed with the microarray assay. The candidate genes were screened by differentially expressed genes (DEGs) analysis and then validated by quantitative real-time polymerase chain reaction (qPCR) in a validation cohort. A receiver operating characteristic (ROC) curve was used to evaluate gene performance in predicting therapeutic effect on RASi reducing proteinuria in IgAN patients. RESULTS ECE1 and PDE1A mRNAs were significantly different among the three groups, and were gradually decreased among A1, B1 and C1 groups. In the validation cohort, the level of urinary exosomal ECE1 and PDE1A mRNAs were also significantly lower in A2 group compared with C2 group(ECE1, P < 0.001;PDE1A, P < 0.01). Besides, the level of ECE1 mRNA was also lower in B2 group compared with C2 group (P < 0.01). The ROC curve verified that urinary exosomal ECE1 and PDE1A gene level predicted RASi efficacy in IgAN patients with area under curve (AUC) 0.68 and 0.63 respectively. CONCLUSION Urinary exosomal ECE1 and PDE1A mRNAs expression can serve as potential biomarkers for predicting the RASi efficacy to reduce proteinuria in IgAN patients.
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Affiliation(s)
- Bingru Zhao
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China
| | - Minzhou Wang
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China
| | - Yue Cong
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China; Department of Emergency Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ahui Song
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China
| | - Jiayue Lu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China
| | - Kewei Xie
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China
| | - Huili Dai
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China; Central Laboratory, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
| | - Leyi Gu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University, School of Medicine, China.
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9
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Chiu AW, Bredenkamp N. Sparsentan: A First-in-Class Dual Endothelin and Angiotensin II Receptor Antagonist. Ann Pharmacother 2024; 58:645-656. [PMID: 37706310 DOI: 10.1177/10600280231198925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2023] Open
Abstract
OBJECTIVE To provide an overview of the guidelines on the management of immunoglobulin A nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS), review the evidence for sparsentan, and discuss its place in therapy. DATA SOURCES A literature search was conducted using MEDLINE, EMBASE, and clinicaltrials.gov using the search terms "sparsentan" and "RE-021" up to the end of Jun 2023. STUDY SELECTION AND DATA EXTRACTION English studies were included if they evaluated the pharmacology, pharmacokinetics, efficacy, and safety of sparsentan in human subjects. Information from the Food and Drug Administration (FDA) and manufacturer's monograph were also extracted. DATA SYNTHESIS In comparison with irbesartan, sparsentan reduced urine protein-to-creatinine ratio (UPCR) in both IgAN (-49.8% vs -15.1% at interim 36 weeks) and FSGS (-44.8% vs -18.5% at 8 weeks). Hypotension and edema were the most common adverse events in the sparsentan groups. Hepatotoxicity appears to be comparable between sparsentan and irbesartan in short-term results. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS Sparsentan provides a new option for patients with IgAN who are otherwise at high risk of progressive kidney disease. Continued FDA approval is dependent on long-term study results on renal function decline and safety. CONCLUSION Sparsentan reduces proteinuria in IgAN and FSGS, and has expedited approval by the FDA for IgAN in patients at risk of rapid disease progression, generally at urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g. Interim results from PROTECT and results from DUET showed promise for improving proteinuria in IgAN and FSGS. Long-term renal function benefit and safety data are pending.
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Affiliation(s)
- Ada W Chiu
- Renal Program, Fraser Health Authority, Surrey, BC, Canada
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Zhang Q, Zhang Q, Duan Z, Chen P, Chen JJ, Li MX, Zhang JJ, Huo YH, Zhang WX, Yang C, Zhang Y, Chen X, Cai G. External Validation of the International IgA Nephropathy Prediction Tool in Older Adult Patients. Clin Interv Aging 2024; 19:911-922. [PMID: 38799377 PMCID: PMC11127691 DOI: 10.2147/cia.s455115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 04/30/2024] [Indexed: 05/29/2024] Open
Abstract
Purpose The International IgA Nephropathy Prediction Tool (IIgAN-PT) can predict the risk of End-stage renal disease (ESRD) or estimated glomerular filtration rate (eGFR) decline ≥ 50% for adult IgAN patients. Considering the differential progression between older adult and adult patients, this study aims to externally validate its performance in the older adult cohort. Patients and Methods We analyzed 165 IgAN patients aged 60 and above from six medical centers, categorizing them by their predicted risk. The primary outcome was a ≥50% reduction in estimated glomerular filtration rate (eGFR) or kidney failure. Evaluation of both models involved concordance statistics (C-statistics), time-dependent receiver operating characteristic (ROC) curves, Kaplan-Meier survival curves, and calibration plots. Comparative reclassification was conducted using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Results The study included 165 Chinese patients (median age 64, 60% male), with a median follow-up of 5.1 years. Of these, 21% reached the primary outcome. Both models with or without race demonstrated good discrimination (C-statistics 0.788 and 0.790, respectively). Survival curves for risk groups were well-separated. The full model without race more accurately predicted 5-year risks, whereas the full model with race tended to overestimate risks after 3 years. No significant reclassification improvement was noted in the full model without race (NRI 0.09, 95% CI: -0.27 to 0.34; IDI 0.003, 95% CI: -0.009 to 0.019). Conclusion : Both models exhibited excellent discrimination among older adult IgAN patients. The full model without race demonstrated superior calibration in predicting the 5-year risk.
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Affiliation(s)
- Qiuyue Zhang
- Chinese PLA Medical School, Beijing, People’s Republic of China
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
- National Key Laboratory of Kidney Diseases, Beijing, People’s Republic of China
- National Clinical Research Center for Kidney Diseases, Beijing, People’s Republic of China
- Beijing Key Laboratory of Kidney Diseases Research, Beijing, People’s Republic of China
| | - Qi Zhang
- Department of Nephrology, Capital Medical University Electric Power Teaching Hospital, Beijing, People’s Republic of China
| | - Zhiyu Duan
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
- National Key Laboratory of Kidney Diseases, Beijing, People’s Republic of China
- National Clinical Research Center for Kidney Diseases, Beijing, People’s Republic of China
- Beijing Key Laboratory of Kidney Diseases Research, Beijing, People’s Republic of China
- Department of Nephrology, Fourth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Pu Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
- National Key Laboratory of Kidney Diseases, Beijing, People’s Republic of China
- National Clinical Research Center for Kidney Diseases, Beijing, People’s Republic of China
- Beijing Key Laboratory of Kidney Diseases Research, Beijing, People’s Republic of China
| | - Jing-jing Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
- National Key Laboratory of Kidney Diseases, Beijing, People’s Republic of China
- National Clinical Research Center for Kidney Diseases, Beijing, People’s Republic of China
- Beijing Key Laboratory of Kidney Diseases Research, Beijing, People’s Republic of China
| | - Ming-xv Li
- Department of Nephrology, Sixth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Jing-jie Zhang
- Department of Nephrology, Third Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Yan-hong Huo
- Department of Nephrology, Seventh Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Wu-xing Zhang
- Department of Nephrology, Eighth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Chen Yang
- School of Medicine, Nankai University, Tianjin, People’s Republic of China
| | - Yu Zhang
- School of Medicine, Nankai University, Tianjin, People’s Republic of China
| | - Xiangmei Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
- National Key Laboratory of Kidney Diseases, Beijing, People’s Republic of China
- National Clinical Research Center for Kidney Diseases, Beijing, People’s Republic of China
- Beijing Key Laboratory of Kidney Diseases Research, Beijing, People’s Republic of China
| | - Guangyan Cai
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
- National Key Laboratory of Kidney Diseases, Beijing, People’s Republic of China
- National Clinical Research Center for Kidney Diseases, Beijing, People’s Republic of China
- Beijing Key Laboratory of Kidney Diseases Research, Beijing, People’s Republic of China
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11
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Cetinkaya H, Gursu M, Yazici H, Cebeci E, Eren N, Altiparmak MR, Akcay OF, Sahin G, Dheir H, Basturk T, Atilgan KG, Aydemir N, Turgutalp K, Yilmaz M, Sirali SK, Tatar E, Boz EG, Mirioglu S, Kazan S, Aydin E, Aydin Z, Turkmen K, Kutlay S, Karagoz F, Ogutmen MB, Ozturk S, Ozkan O, Yildiz N, Dincer T, Yasar E, Gok M, Turkmen A, Dede F, Derici U. Could mesangial C3 deposition be an independent prognostic marker in immunoglobulin A nephropathy? J Nephrol 2024; 37:923-932. [PMID: 37947938 DOI: 10.1007/s40620-023-01770-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 08/18/2023] [Indexed: 11/12/2023]
Abstract
BACKGROUND Immunoglobulin A nephropathy (IgAN) is a common primary glomerulonephropathy. There is evidence that mesangial C3 deposition plays a role in the development of the disease. The aim of this study was to examine the effect of C3 deposition on the prognosis of IgAN patients. METHOD The study included 1135 patients with biopsy-confirmed IgAN from the database of the Turkish Nephrology Association Glomerular Diseases Working Group (TSN-GOLD). Patients were excluded from the study if they were aged < 18 or > 75 years or if C3 staining had not been performed in the immunofluorescent analysis. C3 deposition was defined as an immunofluorescence intensity of C3 ≥ 2 + within the mesangium. The primary endpoints were the development of end-stage renal disease, a 30% decrease in glomerular filtration rate compared to the basal value or an elevation in proteinuria to a nephrotic level (3.5 gr/day). RESULTS Mesangial C3 deposition was observed in 603 (53.1%) patients. No statistically significant difference was found at baseline between the groups with and without mesangial C3 deposition, as for age, sex, BMI, proteinuria level, or the presence of hypertension. In the follow-up period with a mean duration of 78 months, no significant difference was found between the two groups regarding the primary endpoints (p = 0.43). A significant correlation between C3 deposition and segmental glomerulosclerosis (S1) according to the Oxford MEST-C classification was found (p = 0.001). CONCLUSION Although a correlation was observed between mesangial C3 deposition and the S1 MEST-C classification, mesangial C3 deposition was not a prognostic factor in IgAN.
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Affiliation(s)
- Hakki Cetinkaya
- Department of Nephrology, Sultan Abdulhamid Han Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
| | - Meltem Gursu
- Medical Faculty, Nephrology, Bezmialem Vakif University, Istanbul, Turkey
| | - Halil Yazici
- Istanbul Medical Faculty, Nephrology, Istanbul University, Istanbul, Turkey
| | - Egemen Cebeci
- Department of Nephrology, Haseki Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Necmi Eren
- Medical Faculty, Nephrology, Kocaeli University, Izmit, Kocaeli, Turkey
| | | | | | - Gulizar Sahin
- Department of Nephrology, Sultan Abdulhamid Han Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Hamad Dheir
- Medical Faculty, Nephrology, Sakarya University, Adapazari, Sakarya, Turkey
| | - Taner Basturk
- Department of Nephrology, Sisli Hamidiye Etfal Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Kadir Gokhan Atilgan
- Department of Nephrology, Diskapi Training and Research Hospital, University of Health Sciences, Ankara, Turkey
| | - Nihal Aydemir
- Department of Nephrology, Ankara Bilkent City Hospital, University of Health Sciences, Ankara, Turkey
| | - Kenan Turgutalp
- Division of Nephrology, Department of Internal Medicine, Mersin University School of Medicine, Mersin, Turkey
| | - Murvet Yilmaz
- Department of Nephrology, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Semahat Karahisar Sirali
- Department of Nephrology, Ankara Training and Research Hospital, University of Health Sciences, Ankara, Turkey
| | - Erhan Tatar
- Department of Nephrology, Bozyaka Training and Research Hospital, University of Health Sciences, Izmir, Turkey
| | - Elif Gullulu Boz
- Division of Nephrology, Department of Internal Medicine, Uludag University School of Medicine, Bursa, Turkey
| | - Safak Mirioglu
- Medical Faculty, Nephrology, Bezmialem Vakif University, Istanbul, Turkey
| | - Sinan Kazan
- Department of Nephrology, Afyonkarahisar School of Medicine, University of Health Sciences, Afyonkarahisar, Turkey
| | - Emre Aydin
- Medical Faculty, Nephrology, Dicle University, Diyarbakir, Turkey
| | - Zeki Aydin
- Department of Nephrology, Darica Farabi Training and Research Hospital, University of Health Sciences, Darica, Kocaeli, Turkey
| | - Kultigin Turkmen
- Meram Medical Faculty, Nephrology, Necmettin Erbakan University, Konya, Turkey
| | - Sim Kutlay
- Medical Faculty, Nephrology, Ankara University, Ankara, Turkey
| | - Ferdi Karagoz
- Medical Faculty, Nephrology, Trakya University, Edirne, Turkey
| | - Melike Betul Ogutmen
- Department of Nephrology, Haydarpasa Numune Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Savas Ozturk
- Istanbul Medical Faculty, Nephrology, Istanbul University, Istanbul, Turkey
| | - Oktay Ozkan
- Department of Nephrology, Haseki Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Nuriye Yildiz
- Medical Faculty, Nephrology, Kocaeli University, Izmit, Kocaeli, Turkey
| | - Tamer Dincer
- Cerrahpasa Medical Faculty, Nephrology, Istanbul University, Istanbul, Turkey
| | - Emre Yasar
- Medical Faculty, Nephrology, Gazi University, Ankara, Turkey
| | - Mahmut Gok
- Department of Nephrology, Sultan Abdulhamid Han Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Aydın Turkmen
- Istanbul Medical Faculty, Nephrology, Istanbul University, Istanbul, Turkey
| | - Fatih Dede
- Department of Nephrology, Ankara Bilkent City Hospital, University of Health Sciences, Ankara, Turkey
| | - Ulver Derici
- Medical Faculty, Nephrology, Gazi University, Ankara, Turkey
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12
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El Labban M, Surani S. Immunoglobulin A glomerulonephropathy: A review. World J Clin Cases 2024; 12:1388-1394. [PMID: 38576821 PMCID: PMC10989439 DOI: 10.12998/wjcc.v12.i8.1388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/27/2024] [Accepted: 02/25/2024] [Indexed: 03/12/2024] Open
Abstract
In this editorial, we comment on the article by Meng et al published in the World Journal of Clinical Cases. We comprehensively review immunoglobulin A nephropathy (IgAN), including epidemiology, clinical presentation, diagnosis, and management. IgAN, also known as Berger's disease, is the most frequent type of primary glomerulonephritis (GN) globally. It is mostly found among the Asian population. The presentation can be variable, from microscopic hematuria to a rapidly progressive GN. Around 50% of patients present with single or recurring episodes of gross hematuria. An upper respiratory infection and tonsillitis often precede these episodes. Around 30% of patients present microscopic hematuria with or without proteinuria, usually detected on routine examination. The diagnosis relies on having a renal biopsy for pathology and immunofluorescence microscopy. We focus on risk stratification and management of IgAN. We provide a review of all the landmark studies to date. According to the 2021 KDIGO (kidney disease: Improving Global Outcomes) guidelines, patients with non-variant form IgAN are first treated conservatively for three to six months. This approach consists of adequate blood pressure control, reduction of proteinuria with renin-angiotensin system blockade, treatment of dyslipidemia, and lifestyle modifications (weight loss, exercise, smoking cessation, and dietary sodium restrictions). Following three to six months of conservative therapy, patients are further classified as high or low risk for disease progression. High-risk patients have proteinuria ≥ 1 g/d or < 1 g/d with significant microscopic hematuria and active inflammation on kidney biopsy. Some experts consider proteinuria ≥ 2 g/d to be very high risk. Patients with high and very high-risk profiles are treated with immunosuppressive therapy. A proteinuria level of < 1 g/d and stable/improved renal function indicates a good treatment response for patients on immunosuppressive therapy.
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Affiliation(s)
- Mohamad El Labban
- Department of Internal Medicine, Mayo Cliic Health System, Mankato, MN 56001, United States
| | - Salim Surani
- Department of Medicine & Pharmacology, Texas A&M University, College Station, TX 77843, United States
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13
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Tunnicliffe DJ, Reid S, Craig JC, Samuels JA, Molony DA, Strippoli GF. Non-immunosuppressive treatment for IgA nephropathy. Cochrane Database Syst Rev 2024; 2:CD003962. [PMID: 38299639 PMCID: PMC10832348 DOI: 10.1002/14651858.cd003962.pub3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2024]
Abstract
BACKGROUND IgA nephropathy (IgAN) is the most common primary glomerular disease, with approximately 20% to 40% of patients progressing to kidney failure within 25 years. Non-immunosuppressive treatment has become a mainstay in the management of IgAN by improving blood pressure (BP) management, decreasing proteinuria, and avoiding the risks of long-term immunosuppressive management. Due to the slowly progressive nature of the disease, clinical trials are often underpowered, and conflicting information about management with non-immunosuppressive treatment is common. This is an update of a Cochrane review, first published in 2011. OBJECTIVES To assess the benefits and harms of non-immunosuppressive treatment for treating IgAN in adults and children. We aimed to examine all non-immunosuppressive therapies (e.g. anticoagulants, antihypertensives, dietary restriction and supplementation, tonsillectomy, and herbal medicines) in the management of IgAN. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to December 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA Randomised controlled trials (RCTs) and quasi-RCTs of non-immunosuppressive agents in adults and children with biopsy-proven IgAN were included. DATA COLLECTION AND ANALYSIS Two authors independently reviewed search results, extracted data and assessed study quality. Results were expressed as mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI) using random-effects meta-analysis. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS This review includes 80 studies (4856 participants), of which 24 new studies (2018 participants) were included in this review update. The risk of bias within the included studies was mostly high or unclear for many of the assessed methodological domains, with poor reporting of important key clinical trial methods in most studies. Antihypertensive therapies were the most examined non-immunosuppressive therapy (37 studies, 1799 participants). Compared to placebo or no treatment, renin-angiotensin system (RAS) inhibition probably decreases proteinuria (3 studies, 199 participants: MD - 0.71 g/24 h, 95% CI -1.04 to -0.39; moderate certainty evidence) but may result in little or no difference to kidney failure or doubling of serum creatinine (SCr), or complete remission of proteinuria (low certainty evidence). Death, remission of haematuria, relapse of proteinuria or > 50% increase in SCr were not reported. Compared to symptomatic treatment, RAS inhibition (3 studies, 168 participants) probably decreases proteinuria (MD -1.16 g/24 h, 95% CI -1.52 to -0.81) and SCr (MD -9.37 µmol/L, 95% CI -71.95 to -6.80) and probably increases creatinine clearance (2 studies, 127 participants: MD 23.26 mL/min, 95% CI 10.40 to 36.12) (all moderate certainty evidence); however, the risk of kidney failure is uncertain (1 study, 34 participants: RR 0.20, 95% CI 0.01 to 3.88; very low certainty evidence). Death, remission of proteinuria or haematuria, or relapse of proteinuria were not reported. The risk of adverse events may be no different with RAS inhibition compared to either placebo or symptomatic treatment (low certainty evidence). In low certainty evidence, tonsillectomy in people with IgAN in addition to standard care may increase remission of proteinuria compared to standard care alone (2 studies, 143 participants: RR 1.90, 95% CI 1.45 to 2.47) and remission of microscopic haematuria (2 studies, 143 participants: RR 1.93, 95% CI 1.47 to 2.53) and may decrease relapse of proteinuria (1 study, 73 participants: RR 0.70, 95% CI 0.57 to 0.85) and relapse of haematuria (1 study, 72 participants: RR 0.70, 95% CI 0.51 to 0.98). Death, kidney failure and a > 50% increase in SCr were not reported. These trials have only been conducted in Japanese people with IgAN, and the findings' generalisability is unclear. Anticoagulant therapy, fish oil, and traditional Chinese medicines exhibited small benefits to kidney function in patients with IgAN when compared to placebo or no treatment. However, compared to standard care, the kidney function benefits are no longer evident. Antimalarial therapy compared to placebo in one study reported an increase in a > 50% reduction of proteinuria (53 participants: RR 3.13 g/24 h, 95% CI 1.17 to 8.36; low certainty evidence). Although, there was uncertainty regarding adverse events from this study due to very few events. AUTHORS' CONCLUSIONS Available RCTs focused on a diverse range of interventions. They were few, small, and of insufficient duration to determine potential long-term benefits on important kidney and cardiovascular outcomes and harms of treatment. Antihypertensive agents appear to be the most beneficial non-immunosuppressive intervention for IgAN. The antihypertensives examined were predominantly angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The benefits of RAS inhibition appear to outweigh the harms in patients with IgAN. The certainty of the evidence of RCTs demonstrating a benefit of tonsillectomy to patients with Japanese patients with IgAN was low. In addition, these findings are inconsistent across observational studies in people with IgAN of other ethnicities; hence, tonsillectomy is not widely recommended, given the potential harm of therapy. The RCT evidence is insufficiently robust to demonstrate efficacy for the other non-immunosuppressive treatments evaluated here.
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Affiliation(s)
| | - Sharon Reid
- Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Jonathan C Craig
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Joshua A Samuels
- Division of Pediatric Nephrology and Hypertension, UT-Houston Health Science Center, Houston, TX, USA
| | - Donald A Molony
- Internal Medicine, UT-Houston Health Science Center, Houston, TX, USA
| | - Giovanni Fm Strippoli
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
- Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
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14
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Caster DJ, Lafayette RA. The Treatment of Primary IgA Nephropathy: Change, Change, Change. Am J Kidney Dis 2024; 83:229-240. [PMID: 37742867 DOI: 10.1053/j.ajkd.2023.08.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 07/20/2023] [Accepted: 08/07/2023] [Indexed: 09/26/2023]
Abstract
IgA nephropathy (IgAN) is the most common glomerular disease in the world. However, the approach to treatment remains controversial. There has been an explosion of clinical trials over the past decade both to further examine corticosteroid use and usher in additional treatment considerations, including 2 newly approved therapies for IgAN. Sodium glucose cotransporter 2 inhibitors are proving to be effective therapy across proteinuric chronic kidney diseases, and IgAN is not likely to be an exception. Further supportive agents are looking highly promising and so are novel agents that specifically focus on the pathophysiology of this disease, including endothelin blockade, complement inhibition, and B-cell targeted strategies. We suggest a present-day approach to treatment of individuals with IgAN, expose the limitations in our knowledge, and discuss new treatments that may arise, hoping they come with evidence about optimal utilization. Change appears to be inevitable for our approach to the treatment of IgA nephropathy. This is truly an exciting and optimistic time.
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Affiliation(s)
- Dawn J Caster
- Division of Nephrology and Hypertension, University of Louisville, Louisville, Kentucky
| | - Richard A Lafayette
- Division of Nephrology, Stanford University Medical Center, Stanford, California.
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15
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Dixon A, Blanchette E, Kendrick J. A lack of KDIGO guidelines for adolescents and young adults with IgA nephropathy. Pediatr Nephrol 2024; 39:297-304. [PMID: 37261517 DOI: 10.1007/s00467-023-06027-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/27/2023] [Accepted: 05/09/2023] [Indexed: 06/02/2023]
Abstract
BACKGROUND IgA nephropathy (IgAN) is one of the most prevalent primary glomerular diseases in children and adolescents. In 2021, The Kidney Disease: Improving Global Outcomes (KDIGO) released Clinical Practice Guidelines for the Management of Glomerular Diseases as an update to the 2012 guidelines. However, the lack of available evidence for the treatment of IgAN in children has led to an absence of treatment recommendations. CLINICAL CASE We present the case of a 19-year-old male with IgAN who was lost to follow-up after an appointment at a children's hospital 3 years prior. He presents for care at an adult hospital after running out of his medications for many months. He is found to have an elevated blood pressure of 152/97 and an elevated creatinine at 0.8 mg/dL. DISCUSSION There is not only a need for treatment guidelines for IgAN in pediatric patients, but also a need for guidelines for adolescent patients with IgAN as they transition from pediatric to adult care. Therefore, we review the KDIGO treatment guidelines for adults with IgAN and the treatment evidence for children with IgAN and discuss the management dilemma that exists for adolescents and young adults (AYA) with IgAN. Specifically, we propose renin-angiotensin-aldosterone blockade (RASB) treatment, irrespective of blood pressure, for AYA with proteinuria >0.5 g/day. We also propose treatment with corticosteroids for patients with proteinuria >1 g/day and/or mesangial hypercellularity. CONCLUSION The formation of treatment guidelines for patients transitioning from pediatric to adult nephrology care is paramount.
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Affiliation(s)
- Angelina Dixon
- Division of Nephrology and Hypertension, University of Colorado-Denver, Aurora, USA.
- Division of Pediatric Nephrology, Children's Hospital Colorado, Aurora, USA.
| | - Eliza Blanchette
- Division of Pediatric Nephrology, Children's Hospital Colorado, Aurora, USA
| | - Jessica Kendrick
- Division of Nephrology and Hypertension, University of Colorado-Denver, Aurora, USA
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16
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El Karoui K, Fervenza FC, De Vriese AS. Treatment of IgA Nephropathy: A Rapidly Evolving Field. J Am Soc Nephrol 2024; 35:103-116. [PMID: 37772889 PMCID: PMC10786616 DOI: 10.1681/asn.0000000000000242] [Citation(s) in RCA: 30] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 09/19/2023] [Indexed: 09/30/2023] Open
Abstract
The pivotal event in the pathophysiology of IgA nephropathy is the binding of circulating IgA-containing immune complexes to mesangial cells, with secondary glomerular and tubulointerstitial inflammation and fibrosis. The paramount difficulty in the management of IgA nephropathy is the heterogeneity in its clinical presentation and prognosis, requiring an individualized treatment approach. Goal-directed supportive care remains the bedrock of therapy for all patients, regardless of risk of progression. Sodium-glucose transporter 2 inhibitors and sparsentan should be integral to contemporary supportive care, particularly in patients with chronic kidney damage. Pending the development of reliable biomarkers, it remains a challenge to identify patients prone to progression due to active disease and most likely to derive a net benefit from immunosuppression. The use of clinical parameters, including the degree of proteinuria, the presence of persistent microscopic hematuria, and the rate of eGFR loss, combined with the mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, crescents score, is currently the best approach. Systemic glucocorticoids are indicated in high-risk patients, but the beneficial effects wane after withdrawal and come at the price of substantial treatment-associated toxicity. Therapies with direct effect on disease pathogenesis are increasingly becoming available. While targeted-release budesonide has garnered the most attention, anti-B-cell strategies and selective complement inhibition will most likely prove their added value. We propose a comprehensive approach that tackles the different targets in the pathophysiology of IgA nephropathy according to their relevance in the individual patient.
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Affiliation(s)
- Khalil El Karoui
- Department of Nephrology, Hôpital Tenon, Sorbonne Université, Paris, France
| | | | - An S. De Vriese
- Division of Nephrology and Infectious Diseases, AZ Sint-Jan Brugge, Brugge, Belgium
- Department of Internal Medicine, Ghent University, Ghent, Belgium
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17
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Williams CEC, Lamond M, Marro J, Chetwynd AJ, Oni L. A narrative review of potential drug treatments for nephritis in children with IgA vasculitis (HSP). Clin Rheumatol 2023; 42:3189-3200. [PMID: 37755547 PMCID: PMC10640478 DOI: 10.1007/s10067-023-06781-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 09/14/2023] [Accepted: 09/15/2023] [Indexed: 09/28/2023]
Abstract
Immunoglobulin A (IgA) vasculitis (IgAV, also known as Henoch-Schoenlein purpura, HSP) is the most common vasculitis of childhood. It usually presents with a simple, self-limiting disease course; however, a small subset of patients may develop kidney involvement (IgAV-N) which occurs 4-12 weeks after disease onset and is the biggest contributor to long-term morbidity. Treatment currently targets patients with established kidney involvement; however; there is a desire to work towards early prevention of inflammation during the window of opportunity between disease presentation and onset of significant nephritis. There are no clinical trials evaluating drugs which may prevent or halt the progression of nephritis in children with IgAV apart from the early use of corticosteroids which have no benefit. This article summarises the latest scientific evidence and clinical trials that support potential therapeutic targets for IgAV-N that are currently being developed based on the evolving understanding of the pathophysiology of IgAV-N. These span the mucosal immunity, B-cell and T-cell modulation, RAAS inhibition, and regulation of complement pathways, amongst others. Novel drugs that may be considered for use in early nephritis include TRF-budesonide; B-cell inhibiting agents including belimumab, telitacicept, blisibimod, VIS649, and BION-1301; B-cell depleting agents such as rituximab, ofatumumab, and bortezomib; sparsentan; angiotensin converting enzyme inhibitors (ACE-Is); and complement pathway inhibitors including avacopan, iptacopan, and narsoplimab. Further clinical trials, as well as pre-clinical scientific studies, are needed to identify mechanistic pathways as there may be an opportunity to prevent nephritis in this condition. Key Points • Kidney involvement is the main cause of long-term morbidity and mortality in IgA vasculitis despite the current treatment recommendations. • The evolving understanding of the pathophysiology of IgA vasculitis is allowing exploration of novel treatment options which target underlying immune pathways. • Novel treatments currently being trialled in IgA nephropathy may have benefit in IgA vasculitis due to the similarities in the underlying pathophysiology, such as TRF-budesonide, B-cell modulators, and complement inhibitors. • Further studies, including clinical trials of novel drugs, are urgently needed to improve the long-term outcomes for children with IgA vasculitis nephritis.
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Affiliation(s)
- Chloe E C Williams
- Royal Liverpool and Broadgreen University Hospital Trusts, Liverpool, UK
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Megan Lamond
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Julien Marro
- School of Medicine, University of Liverpool, Liverpool, UK
| | - Andrew J Chetwynd
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
- Centre for Proteome Research, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Louise Oni
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.
- Department of Paediatric Nephrology, Institute in the Park Building, University of Liverpool, Alder Hey Children's NHS Foundation Trust Hospital, Eaton Road, Liverpool, L12 2AP, UK.
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Amatruda M, Carucci NS, Chimenz R, Conti G. Immunoglobulin A vasculitis nephritis: Current understanding of pathogenesis and treatment. World J Nephrol 2023; 12:82-92. [PMID: 37766840 PMCID: PMC10520755 DOI: 10.5527/wjn.v12.i4.82] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 05/16/2023] [Accepted: 06/12/2023] [Indexed: 09/20/2023] Open
Abstract
The clinical spectrum of immunoglobulin A vasculitis nephritis (IgAVN) ranges from the relatively common transitory microscopic hematuria and/or low-grade proteinuria to nephritic or nephrotic syndrome, rapidly progressive glomerulonephritis, or even renal failure. Clinical and experimental studies have shown a multifactor pathogenesis: Infection triggers, impaired glycosylation of IgA1, complement activation, Toll-like-receptor activation and B cell proliferation. This knowledge can identify IgAVN patients at a greater risk for adverse outcome and increase the evidence for treatment recommendations.
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Affiliation(s)
- Michela Amatruda
- Pediatric Nephrology and Rheumatology Unit, AOU G Martino, University of Messina, Messina 98125, Italy
| | - Nicolina Stefania Carucci
- Pediatric Nephrology and Rheumatology Unit, AOU G Martino, University of Messina, Messina 98125, Italy
| | - Roberto Chimenz
- Pediatric Nephrology and Rheumatology Unit, AOU G Martino, University of Messina, Messina 98125, Italy
| | - Giovanni Conti
- Pediatric Nephrology and Rheumatology Unit, AOU G Martino, University of Messina, Messina 98125, Italy
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19
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Keskinyan VS, Lattanza B, Reid-Adam J. Glomerulonephritis. Pediatr Rev 2023; 44:498-512. [PMID: 37653138 DOI: 10.1542/pir.2021-005259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
Abstract
Glomerulonephritis (GN) encompasses several disorders that cause glomerular inflammation and injury through an interplay of immune-mediated mechanisms, host characteristics, and environmental triggers, such as infections. GN can manifest solely in the kidney or in the setting of a systemic illness, and presentation can range from chronic and relatively asymptomatic hematuria to fulminant renal failure. Classic acute GN is characterized by hematuria, edema, and hypertension, the latter 2 of which are the consequence of sodium and water retention in the setting of renal impairment. Although presenting signs and symptoms and a compatible clinical history can suggest GN, serologic and urinary testing can further refine the differential diagnosis, and renal biopsy can be used for definitive diagnosis. Treatment of GN can include supportive care, renin-angiotensin-aldosterone system blockade, immunomodulatory therapy, and renal transplant. Prognosis is largely dependent on the underlying cause of GN and can vary from a self-limited course to chronic kidney disease. This review focuses on lupus nephritis, IgA nephropathy, IgA vasculitis, and postinfectious GN.
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20
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Lerma EV, Bensink ME, Thakker KM, Lieblich R, Bunke M, Rava A, Wang K, Murphy MV, Oliveri D, Amari DT, Cork DM, Velez JCQ. Impact of Proteinuria and Kidney Function Decline on Health Care Costs and Resource Utilization in Adults With IgA Nephropathy in the United States: A Retrospective Analysis. Kidney Med 2023; 5:100693. [PMID: 37637862 PMCID: PMC10457441 DOI: 10.1016/j.xkme.2023.100693] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023] Open
Abstract
Rationale & Objective Among patients with IgA nephropathy (IgAN), proteinuria and decline in kidney function may be associated with increased economic burden. This study aimed to provide current information on the epidemiology and economic burden of IgAN in the United States. Study Design Retrospective cohort study. Setting & Study Population Overall, 9,984 patients in the Optum's Market Clarity database identified by the presence of at least 2 natural language processing-derived IgAN signs and disease and symptoms terms; 813 with linked claims data included in a health care resource utilization/cost subcohort. Predictor High-risk proteinuria (≥1 g/d), chronic kidney disease (CKD) stage. Outcomes Standardized prevalence, health care resource utilization, costs. Analytical Approach Descriptive statistics for categorical and continuous variables. Direct standardization for prevalence estimation. Generalized linear models for health care resource utilization/costs, reported as per-patient-per-month (PPPM) costs in 2020 US dollars. Results The estimated standardized US prevalence of IgAN (2016-2020) was 329.0 per 1,000,000 persons. High-risk proteinuria (≥1 vs <1 g/d) was associated with a higher mean PPPM number of outpatient visits (3.49 vs 1.74; P = 0.01) and pharmacy claims (3.79 vs 2.41; P = 0.01), contributing to higher mean total costs PPPM ($3,732 vs $1,457; P = 0.01). Furthermore, higher CKD stage was also associated with higher health care resource utilization (number of outpatient visits PPPM, number of pharmacy claims PPPM, proportion of patients with inpatient visits and emergency department visits; P < 0.001) and mean total cost PPPM (from $2,111 CKD stage 1 to $10,703 CKD stage 5/kidney failure; P < 0.001). Limitations Generalizability outside of the catchment group for the database, missing data/errors inherent in retrospective database studies, relatively small sample size, use of Optum Market Clarity standardized pricing algorithms, exclusion of out-of-pocket costs. Conclusions Health care resource utilization and costs were higher for IgAN patients with high-risk proteinuria and worsening kidney function. Treatments that reduce proteinuria and slow CKD disease progression may reduce the economic burden associated with IgAN. Plain-Language Summary Immunoglobulin A nephropathy (IgAN) is a rare kidney disease. Over time, the kidneys may leak protein into the urine (proteinuria). IgAN can lead to kidney failure. Because IgAN is rare, it is hard to know how many people have it. This study used electronic health records to estimate the number of patients with IgAN in the United States, describe the characteristics of patients, and understand their treatments and the costs. The number of patients with IgAN increased between 2016 and 2020. The researchers think this is because doctors learned more about IgAN. Patients with severe disease used more health care resources and had higher costs. The authors believe treatments that slow kidney damage may reduce the cost of treating IgAN.
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Affiliation(s)
- Edgar V. Lerma
- University of Illinois Chicago/Advocate Christ Medical Center, Oak Lawn, IL
| | | | | | | | | | | | | | | | | | | | | | - Juan Carlos Q. Velez
- Department of Nephrology, Ochsner Health, New Orleans, LA
- Ochsner Clinical School, The University of Queensland, Brisbane, QLD, Australia
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21
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Mao Y, Zhou W, Zhou Z, Zhang C, Shen J, Yin L. Treatment and outcome of IgA nephropathy in children from one single center experience. BMC Pediatr 2023; 23:377. [PMID: 37495962 PMCID: PMC10373308 DOI: 10.1186/s12887-023-04195-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 07/18/2023] [Indexed: 07/28/2023] Open
Abstract
BACKGROUND There is no standard recommendation for IgA nephropathy treatment in children. METHODS This is a retrospective study. From 2012 to 2020, newly diagnosed primary IgAN followed up for at least 1 year were enrolled. The correlation of MESTC scores and clinical index including proteinuria, gross hematuria and renal dysfunction was analyzed. Treatment and clinical response of 6 month, 1year and 3 year at follow up were also analyzed. Complete renal remission was calculated with Kaplan-Meier analysis. RESULTS The median follow up was 36 months, from 12 months to 87months in 40 IgAN children. Angiotensin-converting enzyme inhibitor (ACEI) was applied to all patients. 30% received ACEI alone; 15% received glucocorticoids; 37.5% received glucocorticoids plus cyclophosphamide, 17.5% received glucocorticoids plus mycophenolate mofetil. Individuals with diffuse mesangial hypercellularity (M1) were more likely to have nephrotic range proteinuria compared to patients with M0 (80% vs. 20%, P < 0.01). Complete renal remission at 6-month, 1-year and 3-year follow up is 50.25%, 70% and 87.5% respectively. Five-year complete renal remission calculated by Kaplan-Meier analysis is 58.4%. Although without significant difference, there is trend of better survival with complete renal remission in group of nephrotic range proteinuria onset. There is no severe adverse effect. CONCLUSION This study supports the use of glucocorticoids plus immunosuppressive in addition to ACEI in IgA nephrology pediatric patients with proteinuria. We suggest proactive immunosuppressive treatment in IgA nephropathy in children. This is from a single center in China as may not same results in other population.
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Affiliation(s)
- Youying Mao
- Department of Nephrology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Wei Zhou
- Department of Nephrology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Zhengyu Zhou
- Department of Nephrology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Chenxing Zhang
- Department of Nephrology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jiayao Shen
- Department of Nephrology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Lei Yin
- Department of Nephrology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
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22
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Rivetti G, Gizzone P, Di Sessa A, Guarino S, Miraglia Del Giudice E, Marzuillo P. Renin angiotensin aldosterone inhibitors in the treatment of proteinuria in children with congenital anomalies of the kidney and urinary tract: more evidence needed. Expert Rev Clin Pharmacol 2023; 16:791-798. [PMID: 37577983 DOI: 10.1080/17512433.2023.2247985] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/31/2023] [Accepted: 08/11/2023] [Indexed: 08/15/2023]
Abstract
INTRODUCTION Congenital anomalies of the kidney and urinary tract (CAKUT) can be associated with proteinuria, possibly leading to a decline in kidney function. The aim of this review is to evaluate evidence on the efficacy of renin-angiotensin-aldosterone system inhibitors (RAASi) in children affected by CAKUT with proteinuria or chronic kidney disease (CKD). AREAS COVERED We conducted a bibliographic search between 1 December 2022 and 20 February 2023, including randomized controlled trials, case-control studies, observational studies, meta-analyses, and systematic reviews dealing with the efficacy of RAASi in reducing proteinuria and slowing the decline of kidney function in children. EXPERT OPINION RAASi are effective in reducing proteinuria and slowing CKD progression in many renal conditions; however, the efficacy of these drugs in patients affected by CAKUT with proteinuria is still unknown. While waiting for more evidence, when facing a child with CAKUT with isolated proteinuria or with proteinuria and CKD, a 6-12-month trial with RAASi with gradual increase to the maximal tolerated dose should be considered. If no improvement of proteinuria is obtained, the RAASi should be discontinued.
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Affiliation(s)
- Giulio Rivetti
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Pietro Gizzone
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Anna Di Sessa
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Stefano Guarino
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Emanuele Miraglia Del Giudice
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Pierluigi Marzuillo
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
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23
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Cirillo L, Ravaglia F, Errichiello C, Anders HJ, Romagnani P, Becherucci F. Expectations in children with glomerular diseases from SGLT2 inhibitors. Pediatr Nephrol 2022; 37:2997-3008. [PMID: 35286452 DOI: 10.1007/s00467-022-05504-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 02/08/2022] [Accepted: 02/09/2022] [Indexed: 01/10/2023]
Abstract
Chronic kidney disease (CKD) is a global public healthcare concern in the pediatric population, where glomerulopathies represent the second most common cause. Although classification and diagnosis of glomerulopathies still rely mostly on histopathological patterns, patient stratification should complement information supplied by kidney biopsy with clinical data and etiological criteria. Genetic determinants of glomerular injury are particularly relevant in children, with important implications for prognosis and treatment. Targeted therapies addressing the primary cause of the disease are available for a limited number of glomerular diseases. Consequently, in the majority of cases, the treatment of glomerulopathies is actually the treatment of CKD. The efficacy of the currently available strategies is limited, but new prospects evolve. Although the exact mechanisms of action are still under investigation, accumulating data in adults demonstrate the efficacy of sodium-glucose transporter 2 inhibitors (SGLT2i) in slowing the progression of CKD due to diabetic and non-diabetic kidney disease. SGLT2i has proved effective on other comorbidities, such as obesity, glycemic control, and cardiovascular risk that frequently accompany CKD. The use of SGLT2i is not yet approved in children. However, no pathophysiological clues theoretically exclude their application. The hallmark of pediatric CKD is the inevitable imbalance between the metabolic needs of a growing child and the functional capacity of a failing kidney to handle those needs. In this view, developing better strategies to address any modifiable progressor in kidney disease is mandatory, especially considering the long lifespan typical of the pediatric population. By improving the hemodynamic adaptation of the kidney and providing additional beneficial effects on the overall complications of CKD, SGLT2i is a candidate as a potentially innovative drug for the treatment of CKD and glomerular diseases in children.
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Affiliation(s)
- Luigi Cirillo
- Nephrology and Dialysis Unit, Meyer Children's Hospital, Florence, Italy
- Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy
| | | | | | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Paola Romagnani
- Nephrology and Dialysis Unit, Meyer Children's Hospital, Florence, Italy
- Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy
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24
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Ohyama Y, Yamaguchi H, Ogata S, Chiurlia S, Cox SN, Kouri NM, Stangou MJ, Nakajima K, Hayashi H, Inaguma D, Hasegawa M, Yuzawa Y, Tsuboi N, Renfrow MB, Novak J, Papagianni AA, Schena FP, Takahashi K. Racial heterogeneity of IgA1 hinge-region O-glycoforms in patients with IgA nephropathy. iScience 2022; 25:105223. [PMID: 36277451 PMCID: PMC9583103 DOI: 10.1016/j.isci.2022.105223] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 08/22/2022] [Accepted: 09/23/2022] [Indexed: 11/23/2022] Open
Abstract
Galactose (Gal)-deficient IgA1 (Gd-IgA1) is involved in IgA nephropathy (IgAN) pathogenesis. To reflect racial differences in clinical characteristics, we assessed disease- and race-specific heterogeneity in the O-glycosylation of the IgA1 hinge region (HR). We determined serum Gd-IgA1 levels in Caucasians (healthy controls [HCs], n = 31; IgAN patients, n = 63) and Asians (HCs, n = 20; IgAN patients, n = 60) and analyzed profiles of serum IgA1 HR O-glycoforms. Elevated serum Gd-IgA1 levels and reduced number of Gal residues per HR were observed in Caucasians. Reduced number of N-acetylgalactosamine (GalNAc) residues per HR and elevated relative abundance of IgA1 with three HR O-glycans were common features in IgAN patients; these features were associated with elevated blood pressure and reduced renal function. We speculate that the mechanisms underlying the reduced GalNAc content in IgA1 HR may be relevant to IgAN pathogenesis.
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Affiliation(s)
- Yukako Ohyama
- Department of Biomedical Molecular Sciences, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
| | - Hisateru Yamaguchi
- Department of Nursing, Yokkaichi Nursing and Medical Care University, Yokkaichi, Mie 512-8045, Japan
| | - Soshiro Ogata
- Preventive Medicine and Epidemiology, National Cerebral and Cardiovascular Center, Suita, Osaka 564-8565, Japan
| | - Samantha Chiurlia
- University of Bari and Schena Foundation, Valenzano, Bari 70010, Italy
| | - Sharon N. Cox
- University of Bari and Schena Foundation, Valenzano, Bari 70010, Italy
| | - Nikoletta-Maria Kouri
- Department of Nephrology, Aristotle University of Thessaloniki, Thessaloniki, 54642, Greece
| | - Maria J. Stangou
- Department of Nephrology, Aristotle University of Thessaloniki, Thessaloniki, 54642, Greece
| | - Kazuki Nakajima
- Institute for Glyco-core Research, Gifu University, Gifu, Gifu 501-1193, Japan
| | - Hiroki Hayashi
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
| | - Daijo Inaguma
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
| | - Midori Hasegawa
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
| | - Yukio Yuzawa
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
| | - Naotake Tsuboi
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
| | - Matthew B. Renfrow
- Departments of Biochemistry and Molecular Genetics and Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Jan Novak
- Departments of Biochemistry and Molecular Genetics and Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | | | | | - Kazuo Takahashi
- Department of Biomedical Molecular Sciences, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
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25
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The Effectiveness and Safety of Abelmoschus manihot in Treating IgA Nephropathy: A Systematic Review and Meta-Analysis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:9730753. [PMID: 36248420 PMCID: PMC9556210 DOI: 10.1155/2022/9730753] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 08/29/2022] [Accepted: 09/13/2022] [Indexed: 11/21/2022]
Abstract
Introduction IgA nephropathy (IgAN) is a common issue. In China, Abelmoschus manihot (AM) is widely used in the treatment of IgAN. However, their combined effectiveness and safety for this purpose have not yet been explored. AM is an effective medicine for treating IgAN. This meta-analysis aimed to evaluate the effectiveness of AM for IgAN. Materials and Methods The Cochrane Library, PubMed, EMBASE, Allied and Complementary Medicine Database (AMED), Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure Database (CNKI), Chinese Science and Technique Journals Database (VIP), and the Wanfang Database were searched from their inceptions to June 2021. Random clinical trials (RCTs) comparing the effects of AM treatment in patients with IgAN were included. The study evaluated the efficacy or effectiveness of AM for IgAN and had clear outcome data, such as total effectiveness rate or proteinuria. Results A total of 11 RCTs with 850 participants were included in this meta-analysis. The results of the meta-analysis showed that, compared with that of the conventional therapy alone, being combined with conventional treatment was significantly more effective for the total efficacy rate (OR = 4.33; 95% CI = 2.66, 7.04; P < 0.00001) and proteinuria (MD = -0.41 g/24 h; 95% CI = -0.44, -0.38; P < 0.00001) but had no effect on serum creatinine (Scr) (MD = -2.23 μmol/L; 95% CI = -5.90, 1.45; P=0.24), eGFR (MD = -0.45 mL/min·1.73 m2; 95% CI = -1.24, 2.13; P=0.60), Bun (MD = -0.22 mmol/L; 95% CI = -0.59, 0.14; P=0.23), systolic blood pressure (MD = -0.04 mmHg; 95% CI = -2.59, 2.51; P=0.98), diastolic blood pressure (MD = -0.34 mmHg, 95% CI = -1.65, 2.33; P=0.74), systolic blood pressure (MD = -0.04 mmHg, 95% CI = -2.59, 2.51; P=0.98), or serum albumin (MD = 1.70 g/L, 95% CI = -1.06, 4.45; P=0.23). Conclusions AM provided additional benefits to proteinuria individuals with IgAN. However, due to the high clinical heterogeneity and small sample size of the included trials, future studies should conduct more rigorous RCTs on the clinical efficacy and safety of AM and RCTs with a larger sample size involving multicenters.
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Ștefan G, Stancu S, Zugravu A, Petre N, Secăreanu S, Popa O, Capusa C. Immunosuppressive therapy versus supportive care in IgA nephropathy patients with stage 3 and 4 chronic kidney disease. Medicine (Baltimore) 2022; 101:e30422. [PMID: 36086774 PMCID: PMC10980450 DOI: 10.1097/md.0000000000030422] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 07/27/2022] [Indexed: 11/25/2022] Open
Abstract
The use of immunosuppressive therapy for immunoglobulin A nephropathy (IgAN) patients with stage 3 or 4 chronic kidney disease (CKD) is controversial. We performed a monocentric retrospective study on 83 consecutive IgAN patients with stage 3 or 4 CKD and proteinuria ≥0.75 g/d (age 41 [33-56] years, 72% male, estimated glomerular filtration rate 36.1 [25.4-47.5] mL/min/1.73 m2) who received uncontrolled supportive care (Supp) (n = 36), corticosteroids/corticotherapy (CS) (n = 14), or CS combined with monthly pulses of cyclophosphamide (CS + CFM) (n = 33) between 2010 and 2017. Patients were followed until composite endpoint (doubling of serum creatinine, end-stage kidney disease (dialysis or kidney transplant) or death, whichever came first) or end of study (January 2020). Patients were followed for a median of 29 (95% confidence interval = 25.2-32.7) months, and 12 (15%) patients experienced the composite endpoint. Within the limitation of a retrospective study, our results suggest no benefit from immunosuppressive therapy in patients with IgAN with stage 3 and 4 CKD as compared with supportive care. There were no differences between the 3 studied groups regarding age, estimated glomerular filtration rate, proteinuria, Oxford classification score, arterial hypertension, and therapy with renin-angiotensin system inhibitors. Mean kidney survival time for the entire cohort was 81.0 (95% confidence interval = 73.1-89.0) months, without significant differences between the 3 groups. In univariate and multivariate Cox regression analysis adjusted for IgAN progression factors, immunosuppressive therapy was not associated with better kidney survival when compared with supportive therapy.
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Affiliation(s)
- Gabriel Ștefan
- University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
- Dr. Carol Davila Teaching Hospital of Nephrology, Bucharest, Romania
| | - Simona Stancu
- University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
- Dr. Carol Davila Teaching Hospital of Nephrology, Bucharest, Romania
| | - Adrian Zugravu
- University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
- Dr. Carol Davila Teaching Hospital of Nephrology, Bucharest, Romania
| | - Nicoleta Petre
- University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
- Dr. Carol Davila Teaching Hospital of Nephrology, Bucharest, Romania
| | - Silviu Secăreanu
- University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
| | - Otilia Popa
- University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
- Dr. Carol Davila Teaching Hospital of Nephrology, Bucharest, Romania
| | - Cristina Capusa
- University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
- Dr. Carol Davila Teaching Hospital of Nephrology, Bucharest, Romania
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27
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Wu J, Wei X, Li J, Gan Y, Zhang R, Han Q, Liang P, Zeng Y, Yang Q. Plasma exosomal IRAK1 can be a potential biomarker for predicting the treatment response to renin-angiotensin system inhibitors in patients with IgA nephropathy. Front Immunol 2022; 13:978315. [PMID: 36091017 PMCID: PMC9459338 DOI: 10.3389/fimmu.2022.978315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 08/09/2022] [Indexed: 11/25/2022] Open
Abstract
Background Renin-angiotensin system inhibitors (RASi) are the first choice and basic therapy for the treatment of IgA nephropathy (IgAN) with proteinuria. However, approximately 40% of patients have no response to RASi treatment. The aim of this study was to screen potential biomarkers for predicting the treatment response of RASi in patients with IgAN. Methods We included IgAN patients who were treatment-naive. They received supportive treatment, including a maximum tolerant dose of RASi for 3 months. According to the degree of decrease in proteinuria after 3 months of follow-up, these patients were divided into a sensitive group and a resistant group. The plasma of the two groups of patients was collected, and the exosomes were extracted for high-throughput sequencing. The screening of hub genes was performed using a weighted gene co-expression network (WGCNA) and filtering differentially expressed genes (DEGs). We randomly selected 20 patients in the sensitive group and 20 patients in the resistant group for hub gene validation by real-time quantitative polymerase chain reaction (qRT−PCR). A receiver operating characteristic (ROC) curve was used to evaluate hub genes that predicted the efficacy of the RASi response among the 40 validation patients. Results After screening 370 IgAN patients according to the inclusion and exclusion criteria and the RASi treatment response evaluation, there were 38 patients in the sensitive group and 32 patients in the resistant group. IRAK1, ABCD1 and PLXNB3 were identified as hub genes by analyzing the high-throughput sequencing of the plasma exosomes of the two groups through WGCNA and DEGs screening. The sequencing data were consistent with the validation data showing that these three hub genes were upregulated in the resistant group compared with the sensitive group. The ROC curve indicated that IRAK1 was a good biomarker to predict the therapeutic response of RASi in patients with IgAN. Conclusions Plasma exosomal IRAK1 can be a potential biomarker for predicting the treatment response of RASi in patients with IgAN.
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28
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Yang X, Li Q, He Y, Zhu Y, Yang R, Zhu X, Zheng X, Xiong W, Yang Y. Individualized medication based on pharmacogenomics and treatment progress in children with IgAV nephritis. Front Pharmacol 2022; 13:956397. [PMID: 35935867 PMCID: PMC9355498 DOI: 10.3389/fphar.2022.956397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Immunoglobulin A vasculitis (IgAV) nephritis, also known as Henoch-Schönlein purpura nephritis (HSPN), is a condition in which small blood vessel inflammation and perivascular IgA deposition in the kidney caused by neutrophil activation, which more often leads to chronic kidney disease and accounts for 1%–2% of children with end-stage renal disease (ESRD). The treatment principles recommended by the current management guidelines include general drug treatment, support measures and prevention of sequelae, among which the therapeutic drugs include corticosteroids, immunosuppressive agents and angiotensin system inhibitors. However, the concentration range of immunosuppressive therapy is narrow and the individualized difference is large, and the use of corticosteroids does not seem to improve the persistent nephropathy and prognosis of children with IgAV. Therefore, individualized maintenance treatment of the disease and stable renal prognosis are still difficult problems. Genetic information helps to predict drug response in advance. It has been proved that most gene polymorphisms of cytochrome oxidase P450 and drug transporter can affect drug efficacy and adverse reactions (ADR). Drug therapy based on genetics and pharmacogenomics is beneficial to providing safer and more effective treatment for children. Based on the pathogenesis of IgAV, this paper summarizes the current therapeutic drugs, explores potential therapeutic drugs, and focuses on the therapeutic significance of corticosteroids and immunosuppressants in children with IgAV nephritis at the level of pharmacogenomics. In addition, the individualized application of corticosteroids and immunosuppressants in children with different genotypes was analyzed, in order to provide a more comprehensive reference for the individualized treatment of IgAV nephritis in children.
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Affiliation(s)
- Xuerong Yang
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Qi Li
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuanyuan He
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yulian Zhu
- Department of Pharmacy, Ziyang People’s Hospital, Ziyang, China
| | - Rou Yang
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaoshi Zhu
- Department of Pediatrics, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, China
| | - Xi Zheng
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Wei Xiong
- Department of Hepatobiliary Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, China
- *Correspondence: Wei Xiong, ; Yong Yang,
| | - Yong Yang
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- *Correspondence: Wei Xiong, ; Yong Yang,
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Management of IgA Nephropathy in Pediatric Patients. CHILDREN 2022; 9:children9050653. [PMID: 35626829 PMCID: PMC9139388 DOI: 10.3390/children9050653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 11/17/2022]
Abstract
The onset of IgA nephritis in childhood and adolescence often develops into chronic glomerulonephritis with declining renal function. Although these long-term consequences are known, there is still a lack of evidence-based treatment recommendations in this age group. We report data from 22 pediatric patients who were biopsied to confirm the diagnosis of IgAN at our clinical center. 14 of them were treated with corticosteroids according to the recommendations for IgA nephritis vasculitis of the German Society of Pediatric Nephrology (GPN). Improvement was achieved in the majority of all cases, with a significant reduction in proteinuria five months after initiation of therapy. Our data suggest that treatment regimens for acute IgA nephritis and IgA vasculitis nephritis may be unified and are discussed in the context of current studies.
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Vaz de Castro PAS, Bitencourt L, Pereira BWS, Lima AQR, Hermida HS, Moreira Neto CR, Mestriner MD, Simões E Silva AC. Efficacy and safety of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for IgA nephropathy in children. Pediatr Nephrol 2022; 37:499-508. [PMID: 34686915 DOI: 10.1007/s00467-021-05316-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/12/2021] [Accepted: 09/23/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND IgA nephropathy (IgAN) is one of the most prevalent primary glomerulopathies in children. There are various studies investigating the efficacy of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in adults with IgAN. However, only few studies evaluated the efficacy of these medications in pediatric patients. OBJECTIVE To evaluate the efficacy and safety of ACEI/ARB in children with IgAN. DATA SOURCES Databases including PubMed, Web of Science, Cochrane, Scopus, and Google Scholar were searched between the 1st of April and 20th of July of 2021 using the keywords "IgA Nephropathy," "Berger's Disease," "Angiotensin-Converting Enzyme Inhibitors," "Angiotensin Receptor Antagonists," "Angiotensin II Type 1 Receptor Blockers," and similar entry terms collected from the Medical Subject Headings (MeSH). STUDY ELIGIBILITY CRITERIA Observational studies (case series, case-control, cohort, and cross-sectional) and clinical trials with descriptions of pediatric patients (under 19 years old) with histopathological diagnosis of IgA nephropathy and who received ACEI and/or ARB. PARTICIPANTS AND INTERVENTIONS Pediatric patients (under 19 years old) with histopathological diagnosis of IgA nephropathy and who received ACEI and/or ARB. STUDY APPRAISAL For quality assessment, the Risk of Bias 2 tool (RoB 2), the Risk Of Bias In Non-randomized Studies of Interventions tool (ROBINS-I), the National Institutes of Health (NIH) quality assessment tool, and the Newcastle-Ottawa Scale (NOS) were used. RESULTS After recovering 1,471 studies, only eight, published between 2003 and 2019, met the eligibility criteria and were included in this systematic review. Of the 737 included children in the studies, 202 (25.8%) used ACEI/ARB and were compared with placebo and other therapy regimens. Of the seven studies that evaluated proteinuria, six reported an efficacy of ACEI/ARB in reducing this marker. ACEI/ARB also showed a possible effect in reducing hematuria and oxidative stress. The most common side effect was dizziness. LIMITATIONS The number of studies about the treatment with ACEI/ARB in children with IgAN is scarce. In addition, the studies are very heterogeneous. There are few studies that compared ACEI/ARB with placebo. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS The use of ACEI and/or ARB appears to be safe and to reduce proteinuria in pediatric patients with IgAN. Nonetheless, further randomized controlled trials, with greater methodological rigor and longer follow-up time, are required to establish the efficacy and safety of this therapy in this population. SYSTEMATIC REVIEW REGISTRATION NUMBER The protocol of this systematic literature review was registered in PROSPERO under the number CRD42021245375, and in the OSF registries ( https://osf.io/qft4z/ ) with the registration https://doi.org/10.17605/OSF.IO/VADYR . A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Pedro Alves Soares Vaz de Castro
- Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Alfredo Balena Avenue, 190, 2nd Floor, Room # 281, Belo Horizonte, MG, 30130-100, Brazil
| | - Letícia Bitencourt
- Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Alfredo Balena Avenue, 190, 2nd Floor, Room # 281, Belo Horizonte, MG, 30130-100, Brazil
| | - Bruno Wilnes Simas Pereira
- Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Alfredo Balena Avenue, 190, 2nd Floor, Room # 281, Belo Horizonte, MG, 30130-100, Brazil
| | - Ananda Queiroz Rocha Lima
- Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Alfredo Balena Avenue, 190, 2nd Floor, Room # 281, Belo Horizonte, MG, 30130-100, Brazil
| | - Henrique Santos Hermida
- Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Alfredo Balena Avenue, 190, 2nd Floor, Room # 281, Belo Horizonte, MG, 30130-100, Brazil
| | - Carlos Roberto Moreira Neto
- Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Alfredo Balena Avenue, 190, 2nd Floor, Room # 281, Belo Horizonte, MG, 30130-100, Brazil
| | - Mariana Dinamarco Mestriner
- Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Alfredo Balena Avenue, 190, 2nd Floor, Room # 281, Belo Horizonte, MG, 30130-100, Brazil
| | - Ana Cristina Simões E Silva
- Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Alfredo Balena Avenue, 190, 2nd Floor, Room # 281, Belo Horizonte, MG, 30130-100, Brazil.
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Kurokawa M, Maehara K, Kaku Y, Honjo S. Necessity and choice of therapy for Henoch-Schönlein purpura nephritis. Pediatr Int 2022; 64:e15282. [PMID: 36134650 DOI: 10.1111/ped.15282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 06/16/2022] [Accepted: 06/18/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Henoch-Schönlein purpura nephritis often resolves spontaneously, without treatment, making decisions regarding therapeutic interventions difficult. METHODS Fifty-four patients who were diagnosed as having Henoch-Schönlein purpura nephritis between April 2004 and March 2018, and developed hematuria and/or proteinuria, were studied retrospectively. The observation period ended at the disappearance of hematuria or proteinuria, or the last observation date before December 2019 for each patient. Twenty-four of the patients received no treatment (Group A), 19 underwent renin-angiotensin-aldosterone system inhibitors only (B), 4 experienced steroid pulse therapy and combination therapy only (C) and the remaining 7 received steroid pulse therapy and combination therapy following renin-angiotensin-aldosterone system inhibitors (C). Clinical characteristics were examined according to the treatment method. Survival analysis for persistent urinary abnormalities was performed according to treatment modality, with multiple treatment records created per subject, if necessary. RESULTS The highest urine protein/creatinine levels were significantly higher in groups B and C than in group A. The lowest estimated glomerular filtration rate was not significantly different among the three groups. In groups A and B, proteinuria resolved in >90% of patients. Survival analysis showed that steroid pulse therapy and combination therapy was not related to the better resolution of hematuria or proteinuria than renin-angiotensin-aldosterone system inhibitors. CONCLUSIONS Several patients with Henoch-Schönlein purpura nephritis went into remission either without treatment or with renin-angiotensin-aldosterone system inhibitors alone. The treatment plan for patients with Henoch-Schönlein purpura nephritis needs to be determined carefully.
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Affiliation(s)
- Mari Kurokawa
- Department of Nephrology, Fukuoka Children's Hospital, Fukuoka, Japan.,Division of Pediatrics, National Hospital Organization Fukuokahigashi Medical Center, Koga, Japan
| | - Kenji Maehara
- Department of Nephrology, Fukuoka Children's Hospital, Fukuoka, Japan
| | - Yoshitsugu Kaku
- Department of Nephrology, Fukuoka Children's Hospital, Fukuoka, Japan
| | - Satoshi Honjo
- Department of Pediatrics, National Hospital Organization, Fukuoka National Hospital, Fukuoka, Japan
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Yang J, Okpe A, Pathak A. In Every Man, There Is a Child: Henoch-Schönlein Purpura in an Adult With Liver Cirrhosis. Cureus 2021; 13:e18270. [PMID: 34692357 PMCID: PMC8526072 DOI: 10.7759/cureus.18270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2021] [Indexed: 11/17/2022] Open
Abstract
Henoch-Schönlein purpura (HSP), also known as immunoglobulin A (IgA) vasculitis, is a small-vessel vasculitis characterized by IgA deposits in various organs in the body producing a unique constellation of symptoms. This disease predominantly affects the skin (palpable purpura), joints (arthritis/arthralgia), gut (abdominal pain), and kidneys (nephritic syndrome-IgA nephropathy [IgAN]). The pathogenesis of HSP in children is usually secondary to an immune reaction after viral infections. In adults, few cases of HSP/IgA vasculitis have been reported secondary to altered metabolism of IgA in patients with alcoholic liver cirrhosis. Here, we report an unusual case of HSP/IgA vasculitis. The patient presented with signs of alcoholic liver cirrhosis with abdominal pain and ascites along with a lower extremity purpuric rash. The patient had significant findings of liver cirrhosis with radiographic evidence of cirrhotic liver with esophageal varices and splenorenal shunt and elevated serum ascites albumin gradient. Urinalysis revealed proteinuria with microscopic hematuria, further evaluated with a kidney biopsy. Microscopic analysis revealed focal segmental endocapillary and extracapillary proliferative glomerulonephritis with focal necrotizing features, consistent with IgAN/HSP nephritis. Treatment was initiated with high-dose steroids and cyclophosphamide infusions. Alcohol-induced endotoxin release and inflammation lead to high amounts of circulating IgA due to increased intestinal permeability and reduced hepatic clearance. Further disease development is caused by IgA deposits in affected organs (skin and kidney in our case). We hypothesize that the development of disease for the patient was secondary to altered IgA processing in decompensated alcoholic cirrhosis.
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Affiliation(s)
- Jiajia Yang
- Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, USA
| | - Andrew Okpe
- Internal Medicine, St. Peter's University Hospital, New Brunswick, USA
| | - Amogh Pathak
- Internal Medicine, St. Peter's University Hospital, New Brunswick, USA
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33
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Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, Cook HT, Fervenza FC, Gibson KL, Glassock RJ, Jayne DR, Jha V, Liew A, Liu ZH, Mejía-Vilet JM, Nester CM, Radhakrishnan J, Rave EM, Reich HN, Ronco P, Sanders JSF, Sethi S, Suzuki Y, Tang SC, Tesar V, Vivarelli M, Wetzels JF, Floege J. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int 2021; 100:S1-S276. [PMID: 34556256 DOI: 10.1016/j.kint.2021.05.021] [Citation(s) in RCA: 1092] [Impact Index Per Article: 273.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 05/25/2021] [Indexed: 12/13/2022]
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Non-immunosuppressive therapies for childhood IgA nephropathy. Pediatr Nephrol 2021; 36:3057-3065. [PMID: 33594462 DOI: 10.1007/s00467-021-04954-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 01/06/2021] [Accepted: 01/15/2021] [Indexed: 10/22/2022]
Abstract
IgA nephropathy (IgAN) is the most common chronic primary glomerulonephritis in both children and adults, and 20-30% of patients with persistent hematuria/proteinuria progress to kidney failure within 20 years. In Japan, most cases of childhood IgAN are detected by school screening programs during the early onset of the disease when hematuria/proteinuria are asymptomatic and kidney function is normal. Therefore, it is possible to follow the detailed clinical course and appropriate therapeutic interventions from early onset of the disease. Data on non-immunosuppressive therapies for children with IgAN are highly limited. The Japanese Pediatric IgA Nephropathy Treatment Study Group was organized in 1989 to conduct clinical trials and accumulate data on treatments for childhood IgAN. In this review, we focus on non-immunosuppressive therapies, notably with renin-angiotensin-aldosterone system (RAAS) inhibitors for childhood IgAN and related clinical trials conducted primarily in Japan. We also describe the anti-inflammatory and antiproteinuric effects of RAAS inhibitors in IgAN, differences in treatment regimens because of the acute and active pathological features of childhood IgAN, adverse events of RAAS inhibitors, other non-immunosuppressive treatment options, and future directions.
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Abstract
Immunoglobulin A (IgA) vasculitis (IgAV), previously called Henoch-Schönlein purpura, is characterized by IgA-dominant immune deposits affecting small vessels and often involves the skin, gastrointestinal tract, joints, and kidneys. IgAV is the most common cause of systemic vasculitis in children. The long-term prognosis is dependent on renal involvement: IgAV with nephritis (IgAVN) can progress to renal failure. IgAVN is an inflammatory disease, providing a rationale for the use of corticosteroids. However, data supporting the use of corticosteroids in patients with established IgAVN of any severity remain limited, although most clinicians use them. Even in patients with severe forms of IgAVN, methylprednisolone pulses added to oral corticosteroids appears to improve renal outcomes. Considering the multihit hypothesis for the pathogenesis of IgAVN, involving many other immune agents, there is a strong rationale for the use of other immunosuppressive drugs in patients with IgAVN, including mycophenolic acid, cyclophosphamide, rituximab, calcineurin inhibitors, and complement inhibitors. Thus, these immunosuppressive treatments have also been evaluated in IgAVN, usually in corticosteroid-dependent or corticosteroid-resistant forms and in small retrospective studies. However, their efficacy has not been proven. Thus, the risk of progression to renal failure and the ongoing debate about the best management of IgAVN justifies the interest in investigating and identifying treatments that can potentially preserve renal function in patients with IgAVN. This review reports on the efficacy of the different drugs currently used for the treatment of IgAVN in adults and children.
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36
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Huo Z, Ye H, Ye P, Xiao G, Zhang Z, Kong Y. Comparative efficacy of different renin angiotensin system blockade therapies in patients with IgA nephropathy: a Bayesian network meta-analysis of 17 RCTs. PeerJ 2021; 9:e11661. [PMID: 34268008 PMCID: PMC8269645 DOI: 10.7717/peerj.11661] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 06/01/2021] [Indexed: 12/27/2022] Open
Abstract
Background IgA nephropathy (IgAN) is still one of the most prevalent forms of primary glomerulonephritis globally. However, no guidelines have clearly indicated which kinds of renin angiotensin system blockade therapies (ACEIs or ARBs or their combination) in patients with IgAN result in a greater reduction in proteinuria and a better preservation of kidney function. Thus, we conducted a Bayesian network analysis to evaluate the relative effects of these three therapy regimens in patients with IgAN. Methods The protocol was registered in PROSPERO with ID CRD42017073726. We comprehensively searched the PubMed, the Cochrane Library, Embase, China Biology Medicine disc, WanFang and CNKI databases for studies published since 1993 as well as some grey literature according to PICOS strategies. Pairwise meta-analysis and Bayesian network analysis were conducted to evaluate the effect of different regimens. Results Seventeen randomized controlled trials (RCTs) involving 1,006 patients were analyzed. Co-administration of ACEIs and ARBs had the highest probability (92%) of being the most effective therapy for reducing proteinuria and blood pressure, but ACEIs would be the most appropriate choice for protecting kidney function in IgAN. Conclusion The combination of ACEIs and ARBs seems to have a significantly better antiproteinuric effect and a greater reduction of blood pressure than ACEI or ARB monotherapy in IgAN. ACEIs appear to be a more renoprotective therapy regimen among three therapies.
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Affiliation(s)
- Zhihao Huo
- Nephrology Department, The First People's Hospital of Foshan, Foshan, China.,National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Clinical Research Center for Kidney Disease, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huizhen Ye
- Nephrology Department, The First People's Hospital of Foshan, Foshan, China.,Staff Health Care Department, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Peiyi Ye
- Nephrology Department, The First People's Hospital of Foshan, Foshan, China
| | - Guanqing Xiao
- Nephrology Department, The First People's Hospital of Foshan, Foshan, China
| | - Zhe Zhang
- Nephrology Department, The First People's Hospital of Foshan, Foshan, China
| | - Yaozhong Kong
- Nephrology Department, The First People's Hospital of Foshan, Foshan, China
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Ogura S, Moriyama T, Miyabe Y, Karasawa K, Nitta K. Evaluation of appropriate treatment for IgA nephropathy with mild proteinuria and normal renal function. Clin Exp Nephrol 2021; 25:1103-1110. [PMID: 34101029 DOI: 10.1007/s10157-021-02086-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 05/27/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND Tonsillectomy and steroid pulse therapy (TSP) for immunoglobulin A nephropathy (IgAN) is frequently employed in many Japanese institutions; however, performing this invasive treatment in patients with mild IgAN is controversial. This study aimed to evaluate the appropriate treatment for IgAN patients with mild proteinuria. METHODS In this retrospective cohort analysis, 122 IgAN patients with mild proteinuria (0.5-1.0 g/day) and estimated glomerular filtration rate of ≥ 60 mL/min/1.73 m2 were classified into three groups as follows: patients treated with TSP (n = 32), oral prednisolone (oPSL, n = 33), and conservative therapy (CONS, n = 47). The clinical and histological backgrounds, 5-year remission rates of urinary findings, and 10-year renal survival rates were analyzed. RESULTS The backgrounds were similar among the three groups. The remission rates of hematuria, proteinuria, and both were significantly higher for TSP and oPSL than for CONS; however, they were similar for TSP and oPSL. In the multivariate Cox regression analysis, TSP and oPSL were independent factors for the remission of urinary findings compared with CONS; however, the relapse rates of urinary abnormalities were similar among the three groups. No patient progressed to end-stage renal disease (ESRD) within 10 years. Adverse effects of corticosteroid therapy were significantly more frequent in oPSL than in TSP. CONCLUSION In IgAN patients with mild proteinuria and stable renal function, similar to oPSL, TSP showed higher remission rates of hematuria and/or proteinuria than CONS, and no case progressed to ESRD regardless of the treatment methods. Therefore, appropriate treatments should be carefully considered for each patient.
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Affiliation(s)
- Shota Ogura
- Department of Nephrology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Takahito Moriyama
- Department of Nephrology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
| | - Yoei Miyabe
- Department of Nephrology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Kazunori Karasawa
- Department of Nephrology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Kosaku Nitta
- Department of Nephrology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
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IgA Vasculitis and IgA Nephropathy: Same Disease? J Clin Med 2021; 10:jcm10112310. [PMID: 34070665 PMCID: PMC8197792 DOI: 10.3390/jcm10112310] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 12/14/2022] Open
Abstract
Many authors suggested that IgA Vasculitis (IgAV) and IgA Nephropathy (IgAN) would be two clinical manifestations of the same disease; in particular, that IgAV would be the systemic form of the IgAN. A limited number of studies have included sufficient children or adults with IgAN or IgAV (with or without nephropathy) and followed long enough to conclude on differences or similarities in terms of clinical, biological or histological presentation, physiopathology, genetics or prognosis. All therapeutic trials available on IgAN excluded patients with vasculitis. IgAV and IgAN could represent different extremities of a continuous spectrum of the same disease. Due to skin rash, patients with IgAV are diagnosed precociously. Conversely, because of the absence of any clinical signs, a renal biopsy is practiced for patients with an IgAN to confirm nephropathy at any time of the evolution of the disease, which could explain the frequent chronic lesions at diagnosis. Nevertheless, the question that remains unsolved is why do patients with IgAN not have skin lesions and some patients with IgAV not have nephropathy? Larger clinical studies are needed, including both diseases, with a common histological classification, and stratified on age and genetic background to assess renal prognosis and therapeutic strategies.
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39
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Wheeler DC, Toto RD, Stefánsson BV, Jongs N, Chertow GM, Greene T, Hou FF, McMurray JJV, Pecoits-Filho R, Correa-Rotter R, Rossing P, Sjöström CD, Umanath K, Langkilde AM, Heerspink HJL. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int 2021; 100:215-224. [PMID: 33878338 DOI: 10.1016/j.kint.2021.03.033] [Citation(s) in RCA: 239] [Impact Index Per Article: 59.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/05/2021] [Accepted: 03/19/2021] [Indexed: 01/06/2023]
Abstract
Immunoglobulin A (IgA) nephropathy is a common form of glomerulonephritis, which despite use of renin-angiotensin-aldosterone-system blockers and immunosuppressants, often progresses to kidney failure. In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial, dapagliflozin reduced the risk of kidney failure and prolonged survival in participants with chronic kidney disease with and without type 2 diabetes, including those with IgA nephropathy. Participants with estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio 200-5000 mg/g (22.6-565 mg/mol) were randomized to dapagliflozin 10mg or placebo, as adjunct to standard care. The primary composite endpoint was a sustained decline in eGFR of 50% or more, end-stage kidney disease, or death from a kidney disease-related or cardiovascular cause. Of 270 participants with IgA nephropathy (254 [94%] confirmed by previous biopsy), 137 were randomized to dapagliflozin and 133 to placebo, and followed for median 2.1 years. Overall, mean age was 51.2 years; mean eGFR, 43.8 mL/min/1.73m2; and median urinary albumin-to-creatinine ratio, 900 mg/g. The primary outcome occurred in six (4%) participants on dapagliflozin and 20 (15%) on placebo (hazard ratio, 0.29; 95% confidence interval, 0.12, 0.73). Mean rates of eGFR decline with dapagliflozin and placebo were -3.5 and -4.7 mL/min/1.73m2/year, respectively. Dapagliflozin reduced the urinary albumin-to-creatinine ratio by 26% relative to placebo. Adverse events leading to study drug discontinuation were similar with dapagliflozin and placebo. There were fewer serious adverse events with dapagliflozin, and no new safety findings in this population. Thus, in participants with IgA nephropathy, dapagliflozin reduced the risk of chronic kidney disease progression with a favorable safety profile.
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Affiliation(s)
- David C Wheeler
- Department of Renal Medicine, University College London, London, UK; The George Institute for Global Health, Sydney, Australia.
| | - Robert D Toto
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Bergur V Stefánsson
- Late-Stage Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Niels Jongs
- Department Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Glenn M Chertow
- Department of Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA
| | - Tom Greene
- Study Design and Biostatistics Center, University of Utah Health Sciences, Salt Lake City, Utah, USA
| | - Fan Fan Hou
- Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, Guangzhou, China
| | - John J V McMurray
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Roberto Pecoits-Filho
- Arbor Research Collaborative for Health, Ann Arbor, Michigan, USA; School of Medicine, Pontifical Catholic University of Paraná, Curitiba, Paraná, Brazil
| | - Ricardo Correa-Rotter
- National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico
| | - Peter Rossing
- Steno Diabetes Center Copenhagen, Gentofte, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - C David Sjöström
- Late-Stage Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Kausik Umanath
- Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, Michigan, USA; Division of Nephrology and Hypertension, Wayne State University, Detroit, Michigan, USA
| | - Anna Maria Langkilde
- Late-Stage Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Hiddo J L Heerspink
- Department Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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New therapeutic perspectives for IgA nephropathy in children. Pediatr Nephrol 2021; 36:497-506. [PMID: 32040630 DOI: 10.1007/s00467-020-04475-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 01/02/2020] [Accepted: 01/07/2020] [Indexed: 12/20/2022]
Abstract
Childhood IgA nephropathy (cIgAN) differs from the adult by having an abrupt clinical onset, often presenting as an acute attack that can progress to a chronic phase. No treatment guidelines have been established for the treatment of cIgAN. Given the severity of acute attack in children, and the number of life-years at stake, pediatricians prescribe immunosuppression in addition to renin-angiotensin system blockade. Non-specific immunosuppressors, such as corticosteroids, have systemic toxic effects, and given recent therapeutic advances in adult glomerulonephritis, new tailored strategies should be expected for children. The mucosal immune system has been highlighted as a key player in IgAN pathogenesis, and several biomarkers have been identified with a direct role in pathogenesis. In this review, we discuss current studies of conventional and novel therapeutic approaches for cIgAN.
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Supportive Management of IgA Nephropathy With Renin-Angiotensin Blockade, the AIIMS Primary IgA Nephropathy Cohort (APPROACH) Study. Kidney Int Rep 2021; 6:1661-1668. [PMID: 34169207 PMCID: PMC8207308 DOI: 10.1016/j.ekir.2021.02.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 01/21/2021] [Accepted: 02/08/2021] [Indexed: 01/13/2023] Open
Abstract
Introduction Renin−angiotensin system (RAS) blockade using angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) is first-line therapy for IgA nephropathy (IgAN). There is a paucity of information on the predictors and magnitude of response to this treatment. Methods In a prospective study, treatment-naive patients with IgAN with urinary protein ≥ 1 g/d and estimated glomerular filtration rate (eGFR) ≥ 30 ml/min per 1.73 m2 received supportive treatment including ACEi (ramipril) or ARB (losartan) in patients intolerant to ACEi, and optimal blood pressure (BP) control to ≤130/80 mm Hg, with a follow-up of 6 months. The primary outcome was remission of proteinuria. Complete remission (CR) was defined as proteinuria < 0.5 g/d and partial remission (PR) as proteinuria < 1g/d with at least a 50% decline from the baseline with stable renal function (≤ 25% reduction in eGFR). Results A total of 96 patients were analyzed, with a mean age of 33.3 ± 10.2 years, baseline eGFR 74.0 ± 30.9 ml/min per 1.73 m2, and urinary protein 2.6 ± 1.2 g/d. In all, 71.9% patients received ≥ 75% of the maximum approved dose of ACEi/ARB. Remission was observed in 36.5% (CR, 6.3%) patients at 3 months and in 55.2% (CR, 31.3%) at 6 months. Patients who failed to achieve remission had lower baseline eGFR (P = 0.002) and serum albumin levels (P< 0.001), asymptomatic hyperuricemia (P < 0.001), and higher proteinuria (P = 0.076). E1 (P= 0.053) and T1/T2 (P = 0.009) lesions were more frequent on histology. The ACEi/ARB had to be discontinued in 17 (17.7%) patients. These patients were older (P= 0.085) with lower eGFR (P < 0.002) and serum albumin levels (P = 0.001) and more E1 (P = 0.012) and T1/T2 (P = 0.001) lesions on histology. Conclusion Meticulous supportive therapy with optimal use of ACEi/ARB achieved remission in half of IgAN patients in this study. Increasing the treatment duration to 6 months improved remission rates. Patients with severe clinical and histological disease were less likely to tolerate and respond to treatment with RAS blockade.
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Gohari A, Matsell DG, Mammen C, Goldman RD. Henoch-Schönlein purpura in children: Use of corticosteroids for prevention and treatment of renal disease. CANADIAN FAMILY PHYSICIAN 2020; 66:895-897. [PMID: 33334956 DOI: 10.46747/cfp.6612895] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
QUESTION A few patients have previously presented to my clinic with palpable purpura, joint inflammation, and severe abdominal pain characteristic of Henoch-Schönlein purpura (HSP). Considering that renal injury is the primary long-term complication of HSP, are corticosteroids effective in preventing or treating renal disease in children with HSP? ANSWER Henoch-Schönlein purpura is self-limiting in 94% of children, but permanent renal injury is reported in one-fifth of children with nephritic or nephrotic features. Corticosteroids have been considered as candidates for preventing and treating renal involvement in HSP. There is a moderate level of evidence to suggest corticosteroids are not effective in preventing renal involvement in HSP. However, based on low-level evidence and similarities with primary immunoglobulin A nephropathy, experts recommend corticosteroids in treating renal involvement in HSP to prevent long-term kidney injury. Dose and duration of therapy should be carefully considered in consultation with a pediatric nephrologist.
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Moran SM, Barbour S, Dipchand C, Garland JS, Hladunewich M, Jauhal A, Kappel JE, Levin A, Pandeya S, Reich HN, Thanabalasingam S, Thomas D, Ma JC, White C. Management of Patients With Glomerulonephritis During the COVID-19 Pandemic: Recommendations From the Canadian Society of Nephrology COVID-19 Rapid Response Team. Can J Kidney Health Dis 2020; 7:2054358120968955. [PMID: 33294202 PMCID: PMC7705766 DOI: 10.1177/2054358120968955] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 10/01/2020] [Indexed: 01/22/2023] Open
Abstract
PURPOSE OF PROGRAM This article will provide guidance on how to best manage patients with glomerulonephritis (GN) during the COVID-19 pandemic. SOURCES OF INFORMATION We reviewed relevant published literature, program-specific documents, and guidance documents from international societies. An informal survey of Canadian nephrologists was conducted to identify practice patterns and expert opinions. We hosted a national webinar with invited input and feedback after webinar. METHODS The Canadian Society of Nephrology (CSN) Board of Directors invited physicians with expertise in GN to contribute. Specific COVID-19-related themes in GN were identified, and consensus-based recommendations were made by this group of nephrologists. The recommendations received further peer input and review by Canadian nephrologists via a CSN-sponsored webinar. This was attended by 150 kidney health care professionals. The final consensus recommendations also incorporated review by Editors of the Canadian Journal of Kidney Health and Disease. KEY FINDINGS We identified 9 areas of GN management that may be affected by the COVID-19 pandemic: (1) clinic visit scheduling, (2) clinic visit type, (3) provision of multidisciplinary care, (4) blood and urine testing, (5) home-based monitoring essentials, (6) immunosuppression, (7) other medications, (8) patient education and support, and (9) employment. LIMITATIONS These recommendations are expert opinion, and are subject to the biases associated with this level of evidence. To expedite the publication of this work, a parallel review process was created that may not be as robust as standard arm's length peer review processes. IMPLICATIONS These recommendations are intended to provide optimal care during the COVID-19 pandemic. Our recommendations may change based on the evolving evidence.
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Affiliation(s)
- Sarah M. Moran
- Division of Nephrology, Queen’s University, Kingston, ON, Canada
| | - Sean Barbour
- Division of Nephrology, The University of British Columbia, Vancouver, BC, Canada
| | | | | | - Michelle Hladunewich
- Division of Nephrology, University of Toronto, ON, Canada
- Ontario Renal Network, Toronto, ON, Canada
| | | | - Joanne E. Kappel
- Division of Nephrology, Department of Medicine, University of Saskatchewan, Saskatoon, Canada
| | - Adeera Levin
- Division of Nephrology, The University of British Columbia, Vancouver, BC, Canada
- Executive Director, BC Renal Programme, Vancouver, BC, Canada
| | | | - Heather N. Reich
- Division of Nephrology, Dalhousie University, Halifax, NS, Canada
| | | | | | | | - Christine White
- Division of Nephrology, Queen’s University, Kingston, ON, Canada
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Shi M, Yu S, Ouyang Y, Jin Y, Chen Z, Wei W, Fang Z, Du W, Wang Z, Weng Q, Tong J, Pan X, Wang W, Krzysztof K, Chen N, Xie J. Increased Lifetime Risk of ESRD in Familial IgA Nephropathy. Kidney Int Rep 2020; 6:91-100. [PMID: 33426388 PMCID: PMC7783566 DOI: 10.1016/j.ekir.2020.10.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/05/2020] [Accepted: 10/13/2020] [Indexed: 01/10/2023] Open
Abstract
Introduction Familial IgA nephropathy (IgAN) has been widely reported. However, its clinicohistologic characteristics and long-term prognosis are not clear. Methods A total of 348 familial IgAN cases from 167 independent families were recruited and their clinicohistologic characteristics as well as lifetime risk of end-stage renal disease (ESRD) were compared to 1116 sporadic IgAN patients from the same geographic region. Results Of all familial IgAN patients, 60 (17%) came from 32 single-generation (SG; all affected individuals are siblings) families, whereas 286 (82%) came from 134 multiple-generation (MG; affected individuals were present in at least 2 consecutive generations) families. The lifetime ESRD risk was significantly higher in familial patients than sporadic ones after adjusting by gender (hazard ratio [HR]=1.40, 95% confidence interval [CI]: 1.12–1.74, P = 0.004), with 5 years younger in median ESRD age (60 years vs. 65 years in familial and sporadic cases separately). Interestingly, among familial patients, we found cases from SG families (vs. MG families: HR = 2.62, 95% CI: 1.59–4.31, P < 0.001) or with early onset (onset age <30 years) (vs. late onset: HR = 4.79, 95% CI: 3.16–7.26, P < 0.001) had higher lifetime ESRD risk. Furthermore, among sporadic patients, men had lower estimated glomerular filtration rate (eGFR), higher urine protein, higher Oxford T score, and higher risk for life span ESRD compared with women (male vs. female, 25% vs. 17%, P = 0.003) whereas these gender differences were not seen in familial patients. Conclusion Familial IgAN cases had poorer renal outcomes and less gender differences compared with sporadic cases. These findings provide evidence that familial disease represent a distinct subtype of more progressive IgAN. Early diagnosis could improve the prognosis of cases with familial IgAN.
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Affiliation(s)
- Manman Shi
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Nephrology, Traditional Chinese Medicine Hospital of Kunshan, Nanjing University of Chinese Medicine, Kunshan, Jiangsu, China
| | - Shuwen Yu
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Ouyang
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuanmeng Jin
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zijin Chen
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenjie Wei
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhengying Fang
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wen Du
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhaohui Wang
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qinjie Weng
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Tong
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoxia Pan
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiming Wang
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kiryluk Krzysztof
- Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA
| | - Nan Chen
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingyuan Xie
- Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Marumoto H, Tsuboi N, Kawamura T, Yokoo T. Tonsillectomy Monotherapy for IgA Nephropathy: A Case Series. Kidney Med 2020; 2:620-628. [PMID: 33089140 PMCID: PMC7568076 DOI: 10.1016/j.xkme.2020.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Rationale & Objective Studies of immunoglobulin A nephropathy (IgAN) have suggested the therapeutic benefit of simultaneously adding tonsillectomy to corticosteroid therapy. However, the efficacy of tonsillectomy monotherapy in the absence of simultaneous use of corticosteroids is unclear. Study Design Patients with IgAN treated with tonsillectomy monotherapy were analyzed retrospectively. Clinical parameters, including kidney function slope, were compared before and after tonsillectomy. Setting & Participants Patients with biopsy-proven IgAN who received tonsillectomy monotherapy at our hospital between 2007 and 2018. Results 20 Japanese patients with IgAN were included in this study (mean follow-up period, 135 months from initial biopsy diagnosis to tonsillectomy). All patients had been treated with renin-angiotensin-aldosterone system inhibitors. 17 patients had a history of induction therapy with corticosteroids. Mean time to tonsillectomy from termination of corticosteroid therapy was 84 months. Hematuria, proteinuria, and clinical remission were achieved in 13 of 17 (76%), 10 of 17 (59%), and 8 of 20 (40%) patients at medians of 3.0, 6.0, and 13.5 months, respectively, after tonsillectomy. The slope of the estimated glomerular filtration rate (eGFR) increased significantly during the 81-month observation period, including the periods before and after tonsillectomy (−2.59 vs 1.05 mL/min/1.73 m2 per year; P < 0.001). The effect on eGFR slope was consistent in 11 patients with reduced GFR (eGFR < 60 mL/min/1.73 m2) at the time of tonsillectomy (−3.07 vs −0.39 mL/min/1.73 m2 per year; P < 0.001). Limitations Small sample size. Lack of a control (no-tonsillectomy) group due to the difficulty of setting the baseline time point (which corresponded to tonsillectomy in our sample). Potential exclusion of patients with the most severe disease who are likely to receive corticosteroids. Lack of generalizability to patients in other countries. Conclusions Tonsillectomy monotherapy may prevent kidney function decline in some patients with IgAN with kidney disease that has been progressive despite long-term application of conventional therapies.
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Affiliation(s)
| | - Nobuo Tsuboi
- Address for Correspondence: Nobuo Tsuboi, MD, PhD, Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, Japan.
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Single versus dual blockade of the renin-angiotensin system in patients with IgA nephropathy. J Nephrol 2020; 33:1231-1239. [PMID: 32856272 PMCID: PMC7701065 DOI: 10.1007/s40620-020-00836-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 08/11/2020] [Indexed: 01/21/2023]
Abstract
Background Inhibitors of the renin-angiotensin system (RAS) are cornerstones of supportive therapy in patients with IgA nephropathy (IgAN). We analyzed the effects of single versus dual RAS blockaQueryde during our randomized STOP-IgAN trial. Methods STOP-IgAN participants with available successive information on their RAS treatment regimen and renal outcomes during the randomized 3-year trial phase were stratified post hoc into two groups, i.e. patients under continuous single or dual RAS blocker therapy over the entire 3 years of the trial phase. Primary and secondary STOP-IgAN trial endpoints, i.e. frequencies of full clinical remission, eGFR-loss ≥ 15 and ≥ 30 ml/min/1.73 m2 and ESRD onset, were analyzed by logistic regression and linear mixed effects models. Results Among the 112 patients included in the present analysis, 82 (73%) were maintained on single and 30 (27%) on dual RAS inhibitor therapy throughout the trial. Neither RAS blocker strategy significantly affected full clinical remission, eGFR-loss rates, onset of ESRD. Proteinuria moderately increased in patients under dual RAS blockade by 0.1 g/g creatinine during the 3-year trial phase. This was particularly evident in patients without additional immunosuppression during the randomized trial phase, where proteinuria increased by 0.2 g/g creatinine in the dual RAS blockade group. In contrast, proteinuria decreased in patients under single RAS blocker therapy by 0.3 g/g creatinine. The course of eGFR remained stable and did not differ between the RAS treatment strategies. Conclusion In the STOP-IgAN cohort, neither RAS blocker regimen altered renal outcomes. Patients on dual RAS blockade even exhibited higher proteinuria over the 3-year trial phase.
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Chen J, Liu S, Xu H, Wang W, Xie Y, Tang W, Yuan Q, Zheng L, Lin L, Fu S, Shen J. Retrospective Analysis of Clinical Outcomes in Patients with Immunoglobulin A Nephropathy and Persistent Hematuria Following Renin-Angiotensin System Blockade. Med Sci Monit 2020; 26:e922839. [PMID: 32822333 PMCID: PMC7456162 DOI: 10.12659/msm.922839] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Background Recent guidelines recommend that patients with immunoglobulin A nephropathy (IgAN) and proteinuria 0.5–1 g/d and >1 g/d be treated with long-term renin–angiotensin system blockade (RASB). This study investigated whether patients with IgAN and persistent hematuria, but without proteinuria, can benefit from RASB. Material/Methods IgAN patients with persistent hematuria at four centers were recruited from January 2013 to December 2018. Patients were divided into those who did and did not receive long-term RASB. The primary outcome was the appearance of proteinuria, and the secondary outcomes were the decreased percentage of hematuria, rate of decline in estimated glomerular filtration rate (eGFR) and final blood pressure. The effects of RASB on these outcomes were assessed by multivariate Cox regression models and propensity score matching. Results Of the 110 eligible patients, 44 (40.0%) received RASB and 66 (60.0%) did not. Treated patients had higher diastolic pressure. The unadjusted primary outcome, the appearance of proteinuria, was significantly less frequent in individuals who were than who were not treated with RASB. Multivariate Cox regression showed that RASB reduced the risk of the primary outcome and the levels of hematuria. The rate of eGFR decline and final blood pressure did not differ in the two groups. Conclusions RASB reduced the risk of proteinuria development and increased the remission of hematuria in patients with IgAN who presented with persistent hematuria alone. RASB, however, did not affect blood pressure in patients without hypertension and did not affect the rate of eGFR decline.
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Affiliation(s)
- Jingjing Chen
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland).,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
| | - Shao Liu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
| | - Hui Xu
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland).,Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
| | - Wei Wang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
| | - Yanyun Xie
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
| | - Wenbin Tang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
| | - Qiongjing Yuan
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
| | - Li Zheng
- Blood Purification Centre, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
| | - Lizhen Lin
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland).,Department of Nutrition, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China (mainland)
| | - Shuangshuang Fu
- Department of Nephrology, Hunan Provincial People's Hospital, Changsha, Hunan, China (mainland)
| | - Jinmei Shen
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
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Crescentic IgA nephropathy in children. Pediatr Nephrol 2020; 35:1005-1014. [PMID: 31993782 DOI: 10.1007/s00467-020-04483-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 12/23/2019] [Accepted: 01/14/2020] [Indexed: 10/25/2022]
Abstract
OBJECTIVES Crescentic IgA nephropathy (C-IgAN) is defined as IgAN with more than 50% of glomeruli showing crescents. C-IgAN in children is rare; we investigate in detail for the first time. METHODS We retrospectively analyzed the 515 consecutive children who were newly diagnosed with biopsy-proven IgAN between June 1976 and May 2010. We compared clinical and pathological findings between C-IgAN and non-C-IgAN. RESULTS Among 515 cases of childhood IgAN, 25 children (4.9%) had C-IgAN. Of these 25, 16 children (64%) were referred to hospitals by annual school screening. Clinical findings showed significant differences in gross hematuria (76 vs. 50%, p = .03), excretion of proteinuria (1.9 vs. 0.5 g/day/m2, p < .0001), eGFR (102 vs. 108 ml/min/1.73 m2, p = .03), and duration from onset to renal biopsy (4.0 vs. 8.0 months, p = .04) between groups. Pathological findings showed significant differences in M1 (88 vs. 55%, p = .02), E1 (83 vs. 53%, p = .008), and presence of tubular atrophy/interstitial fibrosis (88 vs. 53%, p < .0001) between groups. The 16 children with C-IgAN were treated with prednisolone and immunosuppressant. Four cases (16%) reached chronic renal failure (eGFR < 60) at the latest observation (mean observation period: 6.0 ± 3.6 years). Patients with C-IgAN had significantly lower renal survival curve than non-C-IgAN patients according to Kaplan-Meier analysis (77.1% vs. 92.6% at 13 years, p < .0001). Compared with previous reports, however, they had better renal outcome. CONCLUSIONS We confirmed the importance of school screening to find C-IgAN. Although most crescents (mean: 98.1%) of C-IgAN were cellular/fibrocellular, and acute lesions were well modified with combination therapy, the presence of tubular atrophy in C-IgAN may be the reason for poorer prognosis.
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Rauen T, Wied S, Fitzner C, Eitner F, Sommerer C, Zeier M, Otte B, Panzer U, Budde K, Benck U, Mertens PR, Kuhlmann U, Witzke O, Gross O, Vielhauer V, Mann JFE, Hilgers RD, Floege J. After ten years of follow-up, no difference between supportive care plus immunosuppression and supportive care alone in IgA nephropathy. Kidney Int 2020; 98:1044-1052. [PMID: 32450154 DOI: 10.1016/j.kint.2020.04.046] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 04/03/2020] [Accepted: 04/16/2020] [Indexed: 12/22/2022]
Abstract
The randomized, controlled STOP-IgAN trial in patients with IgA nephropathy (IgAN) and substantial proteinuria showed no benefit of immunosuppression added on top of supportive care on renal function over three years. As a follow-up we evaluated renal outcomes in patients over a follow-up of up to ten years in terms of serum creatinine, proteinuria, end-stage kidney disease (ESKD), and death. The adapted primary endpoint was the time to first occurrence of a composite of death, ESKD, or a decline of over 40% in the estimated glomerular filtration rate (eGFR) compared to baseline at randomization into STOP-IgAN. Data were analyzed by Cox-regression models. Follow-up data were available for 149 participants, representing 92% of the patients originally randomized. Median follow-up was 7.4 years (inter quartile range 5.7 to 8.3 years). The primary endpoint was reached in 36 of 72 patients randomized to supportive care and 35 of 77 patients randomized to additional immunosuppression (hazard ratio 1.20; 95% confidence interval 0.75 to 1.92). ESKD occurred in 17 of the patients with supportive care and in 20 of the patients with additional immunosuppression. Additionally, the rates of eGFR loss over 40% and annual eGFR loss did not differ between groups. Two patients died with supportive care and three with additional immunosuppression. Thus, within the limitations of a retrospective study, over a follow-up of up to ten years, and using an adapted primary endpoint, we failed to detect differences in key clinical outcomes in IgAN patients randomized to receive added immunosuppression on top of supportive care versus supportive care alone.
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Affiliation(s)
- Thomas Rauen
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Stephanie Wied
- Department of Medical Statistics, RWTH Aachen University, Aachen, Germany
| | - Christina Fitzner
- Department of Medical Statistics, RWTH Aachen University, Aachen, Germany
| | - Frank Eitner
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany; Bayer AG, Kidney Diseases Research, Wuppertal, Germany
| | - Claudia Sommerer
- Department of Nephrology and Renal Center Heidelberg, University of Heidelberg, Heidelberg, Germany
| | - Martin Zeier
- Department of Nephrology and Renal Center Heidelberg, University of Heidelberg, Heidelberg, Germany
| | - Britta Otte
- Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany
| | - Ulf Panzer
- Division of Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Klemens Budde
- Department of Nephrology, Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Urs Benck
- Department of Medicine V, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
| | - Peter R Mertens
- Department of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, Magdeburg, Germany
| | - Uwe Kuhlmann
- Medical Clinic III, Central Hospital Bremen, Bremen, Germany
| | - Oliver Witzke
- Department of Infectious Diseases, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Oliver Gross
- Clinic for Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany
| | - Volker Vielhauer
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany
| | - Johannes F E Mann
- KfH Kidney Center Munich-Schwabing and Department of Medicine IV, University of Erlangen, Erlangen, Germany
| | | | - Jürgen Floege
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.
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Li P, Lin H, Ni Z, Zhan Y, He Y, Yang H, Fang J, Wang N, Li W, Cai G, Chen Y, Zhang P, Wang X, Chen Q, Li Z, Sun X, Chen X. Efficacy and safety of Abelmoschus manihot for IgA nephropathy: A multicenter randomized clinical trial. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 76:153231. [PMID: 32535481 DOI: 10.1016/j.phymed.2020.153231] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 04/03/2020] [Accepted: 04/17/2020] [Indexed: 06/11/2023]
Abstract
RATIONALE AND OBJECTIVE IgA nephropathy (IgAN) is an important cause for end-stage renal disease worldwide. The treatment for IgAN remains challenging, and few randomized and controlled clinical trials have been conducted to evaluate new therapies. The present study assesses the efficacy and safety of Abelmoschus manihot (AM) in IgAN patients. STUDY DESIGN Randomized, non-inferiority, double-blind, double-dummy multicenter trial. SETTING AND PARTICIPANTS This trial was designed to recruit 1,600 biopsy-proven IgAN patients (proteinuria between 0.5-3.0 g/d and estimated glomerular filtration rate [eGFR] of ≥ 45 ml/min/1.73 m2) across China. INTERVENTIONS The participants were randomized at 1:1 to AM (2.5 g for three times per day) or losartan potassium (100 mg per day) for 48 weeks. OUTCOMES The primary outcome was the change in 24-hour proteinuria from baseline to week 48. The secondary outcomes were the change in eGFR from baseline to week 48, and the incidents of endpoint events (proteinuria ≥ 3.5 g/24 h, doubling of serum creatinine, or receiving renal replacement treatment). RESULTS Among 1,470 randomized patients (mean age, 37.4 [SD, 10.6] years old; 777 [52.9%] were female; mean eGFR, 95.0 [SD, 24.3] mL/min/1.73 m2; mean 24-hour proteinuria, 1.2 [SD, 0.7] g/d), the mean decline in 24-h proteinuria at week 48 was 230 mg and 253 mg in the AM and losartan potassium groups, respectively (P = 0.676). The mean difference in the change in 24-h proteinuria between these two groups was -23.32 mg (95% confident interval: -123.2 to 76.6, p = 0.647). The mean decline in eGFR was 0.41 ml/min/1.73 m2 and 0.76 ml/min/1.73 m2 in the AM and losartan potassium groups, respectively (p = 0.661). The mean difference in the change in eGFR between these two groups was -0.43 ml/min/1.73 m2 (95% confident interval: -1.99 to 1.13, p = 0.589). The incidence of endpoint events was 8.6% in the AM group and 8.2% in the losartan group (p = 0.851). LIMITATIONS The results of the trial may not be generalized to IgAN patients with a proteinuria of > 3.0 g/d and an eGFR of < 45 ml/min/1.73 m2. The long-term benefits of AM in reducing the risk of progressive renal dysfunction remains unclear, based on this 48-week observation. CONCLUSION AM can be recommended as a promising treatment for IgAN patients.
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Affiliation(s)
- Ping Li
- Department of Nephrology, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing 100853, China
| | - Hongli Lin
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, China
| | - Zhaohui Ni
- Department of Nephrology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Yongli Zhan
- Department of Nephrology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Yani He
- Department of Nephrology, Da Ping Hospital of Third Military Medical University, Chongqing, 400042, China
| | - Hongtao Yang
- Department of Nephrology, First Teaching Hospital of Tianjin University of TCM, Tianjin 300192, China
| | - Jingai Fang
- Department of Nephrology, The First Hospital of Shanxi Medical University, Taiyuan 030024, China
| | - Niansong Wang
- Department of Nephrology, The Six Affiliated Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Wenge Li
- Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Guangyan Cai
- Department of Nephrology, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing 100853, China
| | - Yizhi Chen
- Department of Nephrology, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing 100853, China
| | - Peiqing Zhang
- Department of Nephrology, Heilongjiang Provincial Academy of Traditional Chinese Medicine, Heilongjiang, 150036, China
| | - Xiaoqin Wang
- Department of Nephrology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, China
| | - Qinkai Chen
- Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Zhenjiang Li
- Department of Nephrology, Shanxi Provincial People's Hospital, Xi'an, 710068, China
| | - Xuefeng Sun
- Department of Nephrology, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing 100853, China.
| | - Xiangmei Chen
- Department of Nephrology, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing 100853, China.
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